Neurology

Key Facts

Intracerebral haemorrhage (ICH) is the deadliest form of stroke. Despite advances in acute care, mortality remains high. Early aggressive management of blood pressure and anticoagulant reversal are the key modifiable factors in the acute phase.

Epidemiology

~15% of all strokes (~15,000 per year in the UK). Incidence ~25 per 100,000 per year. Mortality ~40% at 30 days, ~55% at 1 year. Only 20% of survivors are functionally independent at 6 months. Incidence higher in Afro-Caribbean and South Asian populations. Rising incidence due to anticoagulant use in aging population.

Aetiology

• Hypertensive vasculopathy (~60%): deep locations (putamen 35%, thalamus 20%, pons 5%, cerebellum 10%)
• Cerebral amyloid angiopathy (~15-20%): lobar haemorrhages in elderly; sporadic or hereditary
• Anticoagulant-related (~10-15%): warfarin, DOACs, heparin
• Vascular malformations: AVM, cavernoma, dural AV fistula (younger patients)
• Other: brain tumour (metastasis, glioma), coagulopathy, vasculitis, cocaine/amphetamine use, haemorrhagic transformation of ischaemic stroke, venous sinus thrombosis

Pathophysiology

Presentation

• Sudden-onset severe headache ("worst headache" - less common than SAH but can occur)
• Rapid-onset focal neurological deficit (similar to ischaemic stroke but often more rapid)
• Vomiting (raised ICP)
• Decreased level of consciousness (earlier and more frequent than ischaemic stroke)
• Seizures (~10% at onset)

Location-Specific Features

• Putaminal: contralateral hemiparesis, hemisensory loss, gaze deviation
• Thalamic: contralateral sensory loss > motor, upgaze palsy, small pupils
• Pontine: quadriplegia, pinpoint pupils, coma (devastating)
• Cerebellar: sudden ataxia, headache, vomiting → rapid deterioration (hydrocephalus/brainstem compression)
• Lobar (CAA): cortical signs depending on location; seizures more common

Red Flags

• Decreasing GCS (haematoma expansion, hydrocephalus)
• Fixed dilated pupil (uncal herniation)
• Anticoagulated patient with sudden neurological deficit
• Young patient with lobar ICH (underlying vascular malformation)

Bedside

• GCS: baseline and serial monitoring
• Blood glucose: exclude hypoglycaemia
• BP: often markedly elevated

Imaging

• CT head (non-contrast): IMMEDIATE - acute blood appears hyperdense (bright white); identify location, volume (ABC/2 method), intraventricular extension, hydrocephalus
• CT angiography: spot sign (contrast extravasation within haematoma) predicts expansion; identify underlying vascular malformation
• MRI (GRE/SWI sequences): cerebral microbleeds (CAA pattern - lobar; hypertensive - deep); cortical superficial siderosis (CAA); identify underlying lesion
• CT/MR venography: if venous sinus thrombosis suspected
• Digital subtraction angiography (DSA): gold standard for AVM/aneurysm if suspected

Bloods

• FBC, coagulation (INR, APTT, fibrinogen): URGENT - guide reversal therapy
• U&Es, LFTs: baseline
• Group and save: for potential surgery
• Drug screen: if cocaine/amphetamine suspected

ICH Score

• ICH Score (Hemphill): predicts 30-day mortality; uses GCS, ICH volume, IVH, infratentorial origin, age >80
  • Score 0: ~0% mortality; Score 5: ~100% mortality

Acute

• Admit to hyperacute stroke unit/neurocritical care
• BP reduction: target <140 mmHg systolic within 1 hour (INTERACT-2 trial)
  • IV labetalol 10-20 mg bolus, repeat every 10-20 min (max 300 mg); or infusion 2 mg/min
  • IV GTN infusion 1-10 mg/hr
  • IV nicardipine infusion 5-15 mg/hr
• Anticoagulant reversal (URGENT):
  • Warfarin: IV vitamin K 5-10 mg + 4-factor PCC (Beriplex) 25-50 IU/kg (do NOT wait for INR result if strongly suspected); target INR <1.5
  • Dabigatran: idarucizumab 5 g IV (specific reversal agent)
  • Anti-Xa agents (rivaroxaban, apixaban, edoxaban): andexanet alfa if available; otherwise PCC 50 IU/kg
  • Heparin: protamine sulphate (1 mg per 100 units heparin given in last 2-3 hours)
• Tranexamic acid: TICH-2 trial showed no overall benefit on functional outcome; may reduce early haematoma expansion but not routinely recommended

Surgical/Interventional

• Neurosurgical referral: all patients with cerebellar haemorrhage (risk of hydrocephalus/brainstem compression), large superficial lobar haemorrhages, hydrocephalus
• External ventricular drain (EVD): for acute hydrocephalus (intraventricular extension)
• Surgical evacuation: cerebellar haematoma >3 cm with deterioration; large lobar haematoma with deterioration; STICH/STICH-2 trials showed no overall benefit of early surgery for supratentorial ICH but benefit in superficial lobar haematomas <1 cm from cortical surface
• Minimally invasive surgery: MISTIE III - stereotactic catheter + alteplase into haematoma; some benefit if residual clot reduced to <15 mL

Secondary Prevention

• BP control: long-term target <130/80
• Anticoagulation restart: controversial; consider restart at 4-8 weeks if high thromboembolic risk (e.g., mechanical valve, high-risk AF) after MDT discussion; LEFT-APPENDAGE CLOSURE (LAA occlusion) may be alternative
• Statin use: controversial after ICH; likely safe for non-CAA ICH
• Investigate underlying cause: AVM, aneurysm, tumour in young patients or atypical location

Referral Criteria

• Neurosurgery: all ICH (especially cerebellar, with hydrocephalus, young patients)
• Hyperacute stroke unit: all ICH patients
• Haematology: anticoagulant reversal advice

30-day mortality ~40%. 1-year mortality ~55%. Only 20% of survivors are functionally independent at 6 months. Haematoma volume >30 mL and GCS <8 predict poor outcome. Intraventricular extension doubles mortality. Cerebellar haemorrhage: rapid deterioration but good outcomes if promptly evacuated. CAA-related ICH has ~10% annual recurrence risk. Anticoagulant-related ICH has higher mortality than spontaneous ICH.

ICH Score (Hemphill)

Hypertensive vs CAA ICH

Key Facts

TIA is a medical emergency and a warning sign of imminent stroke. Rapid assessment and initiation of secondary prevention significantly reduces the early stroke risk. The EXPRESS study showed that urgent treatment reduces 90-day stroke risk by 80%.

Epidemiology

Incidence ~50 per 100,000 per year in the UK. Increases with age. ~15-30% of ischaemic strokes are preceded by TIA. Male predominance. Same risk factor profile as ischaemic stroke.

Aetiology

Same as ischaemic stroke: large artery atherosclerosis (carotid stenosis), cardioembolism (AF), small vessel disease, dissection, and other causes. Amaurosis fugax (transient monocular vision loss) is a specific TIA variant caused by retinal artery emboli from carotid disease.

Pathophysiology

Temporary focal cerebral ischaemia that resolves before permanent infarction occurs. Emboli from carotid atherosclerotic plaque or cardiac source temporarily occlude a cerebral artery and then lyse or fragment. Haemodynamic TIA can occur in severe carotid/vertebrobasilar stenosis with hypotension or positional changes. The ischaemic penumbra is salvaged before progressing to infarction.

Anterior Circulation TIA

• Unilateral weakness (face, arm, leg)
• Speech disturbance (dysphasia)
• Amaurosis fugax: transient monocular vision loss ("curtain coming down") - retinal artery embolism from ipsilateral carotid

Posterior Circulation TIA

• Vertigo, ataxia, diplopia
• Bilateral visual disturbance
• Bilateral weakness/sensory symptoms
• Dysarthria

NOT TIA (Common Mimics)

• Isolated vertigo without other neurological signs
• Syncope/presyncope
• Confusion alone
• Bilateral limb weakness/paraesthesiae (peripheral cause)

Red Flags

• Crescendo TIAs (multiple events in short time - very high imminent stroke risk)
• Amaurosis fugax (ipsilateral carotid stenosis)
• TIA on anticoagulation (may indicate need for alternative strategy)
• Young patient with TIA (dissection, PFO, prothrombotic state)

Urgent (Within 24 Hours)

• MRI brain (DWI): gold standard - confirm no infarction (if DWI positive, reclassify as stroke even if symptoms resolved)
• CT head: if MRI unavailable - exclude haemorrhage/structural lesion
• Carotid duplex USS or CTA: urgent if anterior circulation TIA - assess for carotid stenosis
• ECG: detect AF
• Bloods: FBC, U&Es, glucose, lipids, HbA1c, coagulation, ESR/CRP

Extended

• Echocardiography: TTE ± TOE for embolic source
• Prolonged cardiac monitoring: 72 hours minimum (30-day loop recorder if high suspicion of paroxysmal AF)
• Thrombophilia screen: young patients (<50) without clear aetiology
• Bubble contrast echo: if PFO suspected (cryptogenic)

Risk Stratification

• ABCD² score: guides urgency (but all TIAs should be assessed within 24 hours per NICE NG128)

Immediate

• Aspirin 300 mg stat (after CT/imaging excludes haemorrhage)
• Clopidogrel 300 mg loading then 75 mg OD
• Dual antiplatelet for 21 days (aspirin 75 mg + clopidogrel 75 mg) then switch to clopidogrel 75 mg OD monotherapy (CHANCE/POINT trials; NICE NG128)
• If already on clopidogrel: add aspirin for 21 days
• Do NOT drive: DVLA regulations - must not drive for 1 month after TIA; notify DVLA if group 2 licence

Secondary Prevention

• Clopidogrel 75 mg OD long-term (NICE NG128 first-line antiplatelet)
• Anticoagulation for AF: DOAC preferred; start after imaging confirms no haemorrhage/large infarct (apixaban 5 mg BD, edoxaban 60 mg OD)
• Statin: atorvastatin 20-80 mg OD (start immediately; target >40% LDL reduction)
• Antihypertensive: after acute phase; target <130/80
• Lifestyle: smoking cessation, exercise, diet, weight management, alcohol moderation

Surgical/Interventional

• Carotid endarterectomy: within 2 weeks of event if symptomatic carotid stenosis 50-99% (NASCET criteria); greatest benefit if stenosis >70% (NASCET, ECST trials)
• Carotid stenting: alternative if endarterectomy unsuitable
• PFO closure: consider in young patients with cryptogenic TIA/stroke and PFO (CLOSE, RESPECT trials)

Referral Criteria

• All TIAs: specialist stroke/TIA clinic assessment within 24 hours (NICE NG128)
• Crescendo TIAs: emergency admission
• Vascular surgery: symptomatic carotid stenosis >50%

Without treatment, 7-day stroke risk ~5-10% (higher with ABCD² ≥4). With rapid assessment and treatment (EXPRESS study), 90-day stroke risk reduced by ~80% (from ~10% to ~2%). Long-term annual stroke risk after TIA ~2-4% with optimal secondary prevention. Amaurosis fugax has lower stroke risk than hemispheric TIA but still requires urgent assessment.

ABCD² Score

TIA vs Minor Stroke

Key Facts

SAH is a neurosurgical emergency with high mortality and morbidity. A high index of suspicion is essential - any thunderclap headache must be investigated to exclude SAH. The motto "CT-negative SAH" drives the need for LP if CT is non-diagnostic.

Epidemiology

Incidence ~8-10 per 100,000 per year in UK. Peak age 40-60 years. Female predominance (1.6:1). ~3,000 cases per year in UK. ~3% of all strokes. Mortality ~50% (15% die before reaching hospital, 25% die within 24 hours). 50% of survivors have significant disability.

Aetiology

• Berry (saccular) aneurysm: ~85% - arise at arterial bifurcations in the circle of Willis
• Non-aneurysmal perimesencephalic: ~10% - benign; venous origin; centred on midbrain cisterns; angiography negative; excellent prognosis
• Other: AVM, dissection, dural AV fistula, mycotic aneurysm, coagulopathy, cocaine, pituitary apoplexy
• Risk factors for aneurysm: family history (3× risk if first-degree relative), smoking, hypertension, alcohol excess, autosomal dominant polycystic kidney disease (ADPKD), Ehlers-Danlos type IV, coarctation of the aorta

Pathophysiology

Classic Presentation

• Thunderclap headache: sudden-onset, maximal intensity within seconds; severe; "worst headache of my life"
• Often occipital
• May occur during exertion, straining, or sexual intercourse
• Neck stiffness (meningism - may take hours to develop)
• Photophobia
• Nausea and vomiting
• Loss of consciousness (transient or prolonged)

Associated Signs

• CN III palsy (dilated pupil, ptosis, "down and out" eye): PComA aneurysm compressing CN III
• Focal neurological deficit (depending on location)
• Subhyaloid (pre-retinal) haemorrhage on fundoscopy (Terson syndrome)
• Seizures (~10%)

Red Flags

• Any thunderclap headache (SAH until proven otherwise)
• "Sentinel headache" - minor warning leak days/weeks before major SAH (~30% report preceding headache)
• CN III palsy (PComA aneurysm - may rupture imminently)
• GCS deterioration (rebleeding, hydrocephalus, vasospasm)

Immediate

• CT head (non-contrast): FIRST - sensitivity >95-98% within 6 hours (Fisher/modified Fisher grading); shows hyperdense blood in subarachnoid space, cisterns, fissures
• If CT positive → CT angiography: identify aneurysm (location, size, morphology) - sensitivity >95% for aneurysms >3 mm

If CT Negative (but Clinical Suspicion)

• Lumbar puncture at ≥12 hours post-symptom onset:
  • Xanthochromia on spectrophotometry (NOT visual inspection): presence of oxyhaemoglobin/bilirubin confirms SAH
  • Uniformly bloodied CSF (not decreasing across bottles) - less reliable
  • Opening pressure: may be raised

Further Investigation

• Digital subtraction angiography (DSA): gold standard for aneurysm detection; required if CTA inconclusive; also therapeutic (coiling)
• MRI/MRA: can detect aneurysm and old SAH (FLAIR sensitive to subarachnoid blood)
• Transcranial Doppler (TCD): monitor for vasospasm (MCA velocity >120 cm/s suspicious, >200 cm/s = severe vasospasm)

Bloods

• FBC, coagulation, U&Es: baseline
• Troponin: SAH can cause myocardial injury (neurogenic stunned myocardium)
• Sodium: monitor for hyponatraemia (SIADH or cerebral salt wasting)
• Group and save: for potential surgery

Grading

• WFNS grade (World Federation of Neurosurgical Societies): based on GCS + focal deficit
• Fisher/Modified Fisher grade: based on CT appearance - predicts vasospasm risk

Acute

• Admit to neurosurgical/neurocritical care unit
• Secure airway if GCS ≤8
• Analgesia: paracetamol 1 g QDS, codeine 30-60 mg QDS; avoid NSAIDs (platelet effect)
• Antiemetics: ondansetron 4 mg IV PRN
• Blood pressure: maintain SBP <160 mmHg pre-intervention (reduce rebleeding risk)
• Nimodipine 60 mg PO every 4 hours for 21 days: reduces DCI/vasospasm (British Aneurysm Nimodipine Trial; NICE NG128)
• VTE prophylaxis: pneumatic compression devices (NOT pharmacological until aneurysm secured)
• Stool softeners: prevent straining (lactulose)

Definitive Aneurysm Treatment

• Endovascular coiling: preferred for most aneurysms (ISAT trial - better outcomes than clipping at 1 year); performed by interventional neuroradiology; ideally within 48-72 hours
• Neurosurgical clipping: preferred for certain locations (MCA), wide-necked aneurysms, or failed coiling
• Flow diverters: for giant/complex aneurysms

Delayed Cerebral Ischaemia (Vasospasm)

• Days 4-14: monitor with TCD, clinical assessment
• Nimodipine (already started)
• Triple-H therapy: induced hypertension (vasopressors), haemodilution, hypervolaemia (IV fluids) - controversial but widely used
• Intra-arterial nimodipine/milrinone: via catheter if severe vasospasm
• Balloon angioplasty: for focal vasospasm refractory to medical therapy

Hydrocephalus

• Acute: EVD (external ventricular drain) insertion
• Chronic (weeks-months): VP shunt if persistent

Referral Criteria

• All confirmed SAH: immediate neurosurgical centre transfer
• All thunderclap headaches: urgent investigation (CT ± LP)

Overall mortality ~50% (15% die before hospital, 25% within 24 hours, further 25% within 30 days). Of survivors, ~50% have significant cognitive/neurological disability. Good-grade SAH (WFNS I-II): ~80% good outcome. Poor-grade SAH (WFNS IV-V): ~80% poor outcome. Rebleeding: 4% on day 1, ~1.5% per day for next 14 days without treatment. Vasospasm/DCI occurs in ~30% (peak day 7). Perimesencephalic SAH has excellent prognosis (no rebleeding, no vasospasm).

WFNS Grading

Modified Fisher Grading (Vasospasm Risk)

Common Aneurysm Sites

Key Facts

SDH is one of the commonest neurosurgical conditions. Acute SDH carries high mortality due to associated primary brain injury. Chronic SDH is increasingly common due to aging populations and widespread anticoagulant use.

Epidemiology

Acute SDH: incidence ~5-25 per 100,000 per year; most common in young males (trauma) and elderly (falls). Chronic SDH: incidence ~5-14 per 100,000 per year; incidence rising (aging population, anticoagulant use); mean age >70 years.

Aetiology

• Acute: head trauma (RTC, falls, assaults) - high-velocity injury; may also have associated contusion, DAI, skull fracture
• Chronic: minor or forgotten head trauma (weeks-months prior); risk factors: elderly (cerebral atrophy), anticoagulation, antiplatelet therapy, alcohol excess, CSF shunts (over-drainage), coagulopathy
• Subacute (3 days-3 weeks): transitional phase

Pathophysiology

Acute SDH

• History of significant head trauma
• Reduced GCS (often from the outset - due to associated brain injury)
• Focal neurological deficit (contralateral hemiparesis)
• Ipsilateral fixed dilated pupil (uncal herniation → CN III compression)
• Rapid deterioration

Chronic SDH

• Insidious onset (weeks-months after trivial trauma)
• Fluctuating confusion/drowsiness (often mistaken for dementia or delirium)
• Headache (often mild)
• Personality/behavioural change
• Gait disturbance, falls
• Focal weakness (contralateral hemiparesis)
• Speech disturbance
• Seizures (~10%)

Red Flags

• Decreasing GCS (expanding haematoma, herniation)
• Fixed dilated pupil (uncal herniation)
• Progressive neurological deficit in elderly patient ("treatable dementia")
• Bilateral SDH (5-20% - may present without lateralising signs)

Imaging

• CT head (non-contrast): first-line
  • Acute SDH: crescent-shaped hyperdense (bright) collection; may cross suture lines; look for midline shift, mass effect
  • Subacute SDH (1-3 weeks): isodense (may be hard to see - look for effaced sulci, midline shift)
  • Chronic SDH: hypodense (dark) or mixed density collection; crescent; may be bilateral
  • Measure: maximum thickness, midline shift, mass effect on ventricles
• MRI head: more sensitive than CT (especially for isodense subacute SDH and bilateral collections)

Bloods

• Coagulation (INR, APTT, fibrinogen): URGENT if on anticoagulants
• FBC: platelet count
• U&Es, LFTs: baseline
• Group and save: for potential surgery

Additional

• GCS monitoring: serial neurological observations (neurosurgical chart)
• CT angiography: if vascular malformation suspected (young patient without trauma history)

Acute SDH

• Neurosurgical emergency: craniotomy and evacuation if: GCS ≤8, pupil abnormality, midline shift >5 mm, haematoma thickness >10 mm
• Reverse anticoagulation: PCC for warfarin; idarucizumab for dabigatran; andexanet alfa/PCC for anti-Xa agents
• Manage raised ICP: head elevation 30°, sedation, osmotherapy (mannitol 20% 0.5-1 g/kg or hypertonic saline)
• Supportive: ITU care, neuroprotection, seizure prophylaxis if concern

Chronic SDH

• Conservative: for small, asymptomatic collections; serial CT monitoring; stop/reverse anticoagulation; consider dexamethasone (Dex-CSDH trial - no benefit shown; NOT routinely recommended)
• Surgical: burr hole drainage (1-2 burr holes + irrigation ± subdural drain): first-line for symptomatic chronic SDH; performed under LA or GA; post-op: lie flat for 24-48 hours; subdural drain for 24-48 hours
• Mini-craniotomy: for organised/septated collections not amenable to burr holes
• Middle meningeal artery embolisation: emerging treatment for recurrent chronic SDH (EMBOLISE trial, STEM trial); reduces recurrence
• Recurrence rate: ~10-20% after initial burr hole drainage; risk factors: anticoagulant use, bilateral SDH, recollection on post-op imaging

Referral Criteria

• All acute SDH: immediate neurosurgical referral
• Chronic SDH with symptoms: neurosurgical referral
• All patients on anticoagulants with SDH: urgent anticoagulant reversal + neurosurgical input

Acute SDH: mortality ~50-90% (poor prognosis due to associated primary brain injury); outcome depends more on associated parenchymal injury than the SDH itself. GCS on admission is the strongest prognostic factor. Chronic SDH: excellent prognosis with surgical treatment - ~80-90% good outcome after burr hole drainage. Recurrence rate ~10-20%. Bilateral chronic SDH has higher recurrence. Early mobilisation and rehabilitation improves functional outcomes.

SDH CT Density Over Time

Subdural vs Extradural Haematoma

Key Facts

Extradural haematoma (EDH) is a neurosurgical emergency where prompt recognition and surgical treatment are life-saving. It is classically seen in young patients after temporal bone trauma. The lucid interval is a well-known but not universal feature.

Epidemiology

Incidence ~1-4% of head-injury admissions; overall ~2 per 100,000 per year. Peak age 20-30 years (young adults). Male predominance (4:1). Rare in the very young (<2 years - dura more adherent to skull) and elderly (dura more adherent).

Aetiology

• Arterial (~90%): middle meningeal artery rupture - usually following temporal/parietal skull fracture
• Venous (~10%): dural venous sinus tear (posterior fossa EDH - from transverse sinus) or meningeal vein; these accumulate more slowly
• Skull fracture: present in ~75-95% of adult EDH cases

Pathophysiology

Classic Presentation ("Lucid Interval")

1. Initial injury: brief loss of consciousness (concussion)
2. Lucid interval: apparent recovery (patient alert and orientated) - minutes to hours

Clinical Signs

• Ipsilateral fixed dilated pupil (CN III compression - first sign of uncal herniation)
• Contralateral hemiparesis (cerebral peduncle compression)
• Cushing response: hypertension + bradycardia + irregular respirations (brainstem compression - late and ominous)
• Scalp swelling/bruising over temporal region
• Seizures (~10%)

Important Notes

• Lucid interval occurs in only ~30% - many patients have persistent reduced GCS
• Some patients may not lose consciousness initially ("talk and deteriorate")

Red Flags

• Any head-injury patient who deteriorates after initial improvement
• Fixed dilated pupil in head-injured patient
• Cushing response (imminent brainstem herniation)
• GCS drop ≥2 points (NICE CG176 - urgent CT)

Imaging

• CT head (non-contrast): IMMEDIATE - biconvex (lens-shaped) hyperdense collection; usually temporal/temporoparietal; does NOT cross suture lines; look for:
  • Midline shift (>5 mm = significant)
  • Mass effect on ipsilateral ventricle (compression/effacement)
  • Associated skull fracture
  • Underlying brain injury
• Skull X-ray: NOT indicated (CT is definitive); if done, may show temporal fracture

Bloods

• FBC, coagulation: baseline
• Group and crossmatch: for surgery
• U&Es: baseline

NICE CG176 Indications for CT Head (Head Injury)

• GCS <13 at any point
• GCS <15 at 2 hours post-injury
• Suspected skull fracture
• Post-traumatic seizure
• Focal neurological deficit

• 1 episode of vomiting

• Loss of consciousness/amnesia + age ≥65, coagulopathy, or dangerous mechanism

Emergency

• A-E assessment: protect airway if GCS ≤8 (intubate)
• Immediate CT head: do NOT delay for any reason if clinically suspected
• Emergency craniotomy: for evacuation of haematoma if:
  • Haematoma thickness >15 mm
  • Midline shift >5 mm
  • GCS <9 or deteriorating GCS
  • Pupil abnormality
  • Any symptomatic EDH requires urgent surgical discussion
• Burr hole: may be performed as temporising measure if craniotomy not immediately available ("burr hole and pray")

Intraoperative

• Craniotomy: bone flap raised over haematoma
• Haematoma evacuated
• Bleeding source identified and controlled (middle meningeal artery - coagulation, wax, or ligation)
• Dura may be tacked to skull to prevent reaccumulation

Post-operative

• ITU/HDU monitoring
• Serial neurological observations
• Post-op CT: confirm evacuation, exclude reaccumulation
• Seizure prophylaxis: consider short course (levetiracetam or phenytoin)

Conservative

• Small, asymptomatic EDH (<15 mm, midline shift <5 mm, GCS 15): may be managed conservatively with close observation and serial CT
• Must have neurosurgical availability for emergency surgery

Referral Criteria

• All EDH: immediate neurosurgical referral
• Any deteriorating head-injured patient: immediate CT and neurosurgical contact

With prompt surgical evacuation: mortality <5%; good functional outcome in most cases. Without treatment: mortality approaches 100% (fatal herniation). Pre-operative GCS is the strongest prognostic factor: GCS 8-15 pre-op has excellent outcomes; GCS 3-5 pre-op has ~35% mortality despite surgery. The "talk and die" patient highlights the importance of serial neurological monitoring in all head injuries. Posterior fossa EDH has worse prognosis due to rapid brainstem compression. Overall, EDH has significantly better outcomes than acute SDH (less associated parenchymal injury).

EDH vs SDH Comparison

NICE CG176 CT Head Criteria (Key Points)

Key Facts

Epilepsy is one of the most common serious neurological conditions. Accurate seizure classification is essential as treatment differs by seizure type. Most patients (60-70%) achieve seizure freedom with appropriate medication.

Epidemiology

Prevalence ~1% in UK (~600,000 people). Incidence ~50 per 100,000 per year. Bimodal age distribution: peak in first year of life and >65 years. 25% of new diagnoses are in elderly. Lifetime risk ~3%. Accounts for ~1,000 deaths/year in UK (including ~500 SUDEP).

Aetiology

• Structural: hippocampal sclerosis (mesial temporal lobe epilepsy), cortical dysplasia, tumour, vascular malformation, previous stroke/TBI
• Genetic: idiopathic generalised epilepsies (juvenile myoclonic epilepsy, childhood absence epilepsy), SCN1A (Dravet syndrome)
• Infectious: post-meningitis/encephalitis, neurocysticercosis
• Metabolic: mitochondrial disorders, pyridoxine-dependent epilepsy
• Immune: autoimmune encephalitis (NMDA-R, LGI1, CASPR2)
• Unknown: ~50% of cases have no identified cause

Pathophysiology

Seizures result from abnormal, excessive, synchronous neuronal discharge. This may arise from an imbalance between excitatory (glutamate) and inhibitory (GABA) neurotransmission. Focal seizures originate from a localised network; generalised seizures involve widespread bilateral networks from onset. Epileptogenesis is the process by which a normal brain becomes epileptic (e.g., after head injury, stroke) - involves neuronal reorganisation, gliosis, and altered channel/receptor expression.

Focal Seizures

• Focal aware (previously simple partial): preserved consciousness; motor, sensory, autonomic, or psychic symptoms depending on cortical origin
  • Temporal: déjà vu, rising epigastric sensation, automatisms, emotional changes
  • Frontal: motor (clonic jerking), head/eye turning, vocalisation
  • Parietal: tingling, numbness
  • Occipital: flashing lights, visual hallucinations
• Focal impaired awareness (previously complex partial): impaired consciousness; temporal lobe most common; automatisms (lip-smacking, picking, fumbling)
• Focal to bilateral tonic-clonic: starts focally then generalises

Generalised Seizures

• Absence: brief (5-15 seconds) staring episodes, unresponsive; no post-ictal state; 3 Hz spike-and-wave on EEG
• Myoclonic: sudden brief jerks; common in JME (typically morning myoclonic jerks)
• Tonic: sudden stiffening (often nocturnal, in Lennox-Gastaut)
• Atonic: sudden loss of tone, drop attacks

Red Flags

• New-onset seizures in adult (exclude structural cause - tumour, stroke)
• Seizures with fever in adult (meningitis/encephalitis)
• Progressive neurological deficit between seizures (space-occupying lesion)
• Status epilepticus (seizure >5 minutes or recurrent without recovery)
• Post-ictal Todd's paresis lasting >24 hours (consider stroke)

First Seizure / Suspected Epilepsy

• EEG: should be performed in ALL suspected epilepsy; interictal epileptiform discharges support diagnosis (but normal EEG does NOT exclude epilepsy - ~50% normal on first recording)
  • Focal spikes/sharp waves → focal epilepsy
  • 3 Hz spike-and-wave → childhood absence epilepsy
  • 4-6 Hz polyspike-and-wave → JME
  • Sleep-deprived EEG increases yield
• MRI brain: all adults with epilepsy (NICE NG217); identify structural cause (hippocampal sclerosis, tumour, cortical dysplasia, vascular malformation)
• ECG: exclude cardiac cause of LOC (long QT, Brugada)

Bloods

• Glucose, calcium, sodium, magnesium: metabolic causes
• FBC, LFTs, U&Es: baseline before starting AEDs
• Prolactin: raised 10-20 minutes after GTC (helps distinguish from PNES; limited specificity)

Special Tests

• Video-EEG telemetry: gold standard for seizure classification and diagnosis of PNES
• Neuropsychology: pre-surgical evaluation
• MRI with epilepsy protocol: thin cuts through hippocampi, FLAIR, volumetric
• PET/SPECT: functional imaging for pre-surgical evaluation (identify seizure focus)

Non-pharmacological

• Lifestyle: regular sleep, avoid alcohol excess, stress management
• Seizure diary: track frequency, type, triggers
• Safety advice: avoid swimming alone, heights, open fires; supervised bathing
• DVLA: must not drive until seizure-free for 12 months (group 1) or 10 years off medication (group 2); must inform DVLA
• First aid for seizures: protect from injury, recovery position after convulsion, do NOT restrain or put anything in mouth, call 999 if seizure >5 minutes

Pharmacological (NICE NG217)

Focal seizures:

• Second-line: carbamazepine 100-600 mg BD, oxcarbazepine, zonisamide, lacosamide

Generalised tonic-clonic:

• First-line: sodium valproate 300-1000 mg BD (NOT in women of childbearing potential - MHRA) or lamotrigine (if valproate unsuitable)
• Second-line: levetiracetam, topiramate

Absence:

• First-line: ethosuximide 250-500 mg BD or sodium valproate
• Second-line: lamotrigine (less effective for absences)

Juvenile myoclonic epilepsy (JME):

• First-line: sodium valproate (most effective) or levetiracetam (if valproate unsuitable)
• AVOID: carbamazepine, phenytoin, gabapentin (can worsen myoclonic/absence seizures in generalised epilepsy)

Women of childbearing potential:

• Valproate Pregnancy Prevention Programme (MHRA): must use effective contraception; annual risk acknowledgement form
• Preferred: lamotrigine or levetiracetam
• Folic acid 5 mg/day: all women with epilepsy planning pregnancy (start 3 months pre-conception)

Surgical/Interventional

• Epilepsy surgery: consider referral if drug-resistant epilepsy (failed ≥2 appropriate AEDs); temporal lobe resection for mesial temporal sclerosis (60-70% seizure-free); NICE recommends early referral to tertiary epilepsy centre
• Vagus nerve stimulation (VNS): palliative; reduces seizure frequency by ~50% in ~30-40%
• Ketogenic diet: mainly used in children with drug-resistant epilepsy

Referral Criteria

• First seizure: neurology (seen within 2 weeks - NICE NG217)
• Drug-resistant epilepsy (≥2 AED failures): tertiary epilepsy centre
• Women of childbearing potential on valproate: specialist review
• Diagnostic uncertainty: video-EEG telemetry

60-70% of patients achieve seizure freedom with appropriate AED. ~30% have drug-resistant epilepsy. Epilepsy surgery can achieve 60-70% seizure freedom in temporal lobe epilepsy. SUDEP (Sudden Unexpected Death in Epilepsy): ~1 per 1000 patient-years (higher in drug-resistant epilepsy - up to 1 in 150); risk factors: nocturnal seizures, uncontrolled GTC seizures, polytherapy. Overall life expectancy reduced by ~10 years compared to general population (related to underlying aetiology and SUDEP).

AED Selection Summary

SUDEP Risk Factors

Key Facts

Status epilepticus is a neurological emergency where rapid, protocolised treatment is essential. The longer the seizure continues, the harder it is to terminate and the greater the risk of permanent brain injury. The operational definition of 5 minutes allows earlier intervention.

Epidemiology

Incidence ~10-40 per 100,000 per year. Mortality 10-20% for convulsive SE (higher in elderly and those with underlying structural disease). ~60% of SE occurs in patients without a prior epilepsy diagnosis. Accounts for ~5-10% of epilepsy-related admissions.

Aetiology

• Known epilepsy: medication non-compliance (most common cause in known epileptics), intercurrent illness, sleep deprivation, alcohol
• Acute symptomatic: stroke, traumatic brain injury, CNS infection (meningitis, encephalitis), metabolic (hypoglycaemia, hyponatraemia, hypocalcaemia), drug toxicity/withdrawal (alcohol, benzodiazepines), autoimmune encephalitis
• Remote symptomatic: previous structural brain injury (stroke, TBI) with new trigger
• Febrile SE: in children (see febrile seizures)

Pathophysiology

Prolonged seizure activity causes: (1) progressive loss of GABA-A receptor inhibition (receptor internalisation) - explains why benzodiazepines become less effective with time, (2) upregulation of excitatory NMDA receptors, (3) excitotoxic neuronal death (glutamate-mediated calcium influx), (4) systemic complications: hyperthermia, rhabdomyolysis, lactic acidosis, aspiration, cardiac arrhythmias, cerebral oedema. After ~30 minutes of continuous seizure, irreversible neuronal damage begins.

Convulsive Status Epilepticus (CSE)

• Continuous or repetitive tonic-clonic seizure activity without recovery between episodes
• Patient unconscious between/during seizures
• May evolve from overt convulsions to subtle motor activity ("subtle SE" - twitching, nystagmoid eye movements) as the seizure continues

Non-convulsive Status Epilepticus (NCSE)

• Prolonged altered mental status/confusion without overt convulsions
• May present as unexplained prolonged confusion, behavioural change, or coma
• Diagnosed by EEG (continuous epileptiform discharges)
• Often under-recognised

Red Flags

• Seizure >5 minutes (do not wait for 30 minutes)
• No recovery between seizures
• Evolving to subtle SE (worsening prognosis)
• Hyperthermia (>40°C - poor prognosis)
• Refractory to initial treatment (requires escalation)
• Persistent unexplained confusion (consider NCSE)

Immediate (During Treatment)

• Blood glucose: MUST check immediately - treat hypoglycaemia with 50 mL 20% glucose IV
• ABG/VBG: lactate, pH (acidosis), oxygenation
• FBC, U&Es, calcium, magnesium, LFTs: metabolic causes
• AED levels: if known epileptic (phenytoin, carbamazepine, valproate levels)
• Toxicology screen: if drug overdose/withdrawal suspected
• Blood cultures: if infection suspected

After Stabilisation

• CT head: exclude structural cause (haemorrhage, tumour, abscess)
• MRI brain: more detailed structural assessment
• LP: if CNS infection or autoimmune encephalitis suspected (after CT excludes mass effect)
• EEG: as soon as possible; essential for:
  • Confirming SE if clinically uncertain
  • Diagnosing NCSE
  • Monitoring treatment response in RSE (continuous EEG - aim for burst suppression with anaesthesia)
• Autoimmune encephalitis panel: NMDA-R, LGI1, CASPR2 antibodies (if new-onset refractory SE without clear cause - NORSE)

Stage 1: Early Status (0-5 minutes)

• Secure airway, recovery position
• High-flow oxygen
• Check blood glucose: treat hypoglycaemia (IV glucose 10-20%)
• IV access: 2 large-bore cannulae

Stage 2: Established Status (5-15 minutes - First-line)

• IV lorazepam 4 mg (0.1 mg/kg); repeat once at 10 minutes if seizures continue
• If no IV access: buccal midazolam 10 mg or rectal diazepam 10-20 mg
• Thiamine 250 mg IV (Pabrinex) if alcohol-related or malnourished (BEFORE glucose)

Stage 3: Established Status (15-35 minutes - Second-line)

Choose ONE:

• IV phenytoin 20 mg/kg (max rate 50 mg/min); requires cardiac monitoring (risk of arrhythmia, hypotension); avoid if already on phenytoin
• IV levetiracetam 40-60 mg/kg (max 4.5 g) over 10 minutes; increasingly preferred (fewer cardiac risks)
• IV sodium valproate 40 mg/kg (max 3 g) over 5-10 minutes; avoid in liver disease, pregnancy, mitochondrial disease

Stage 4: Refractory Status Epilepticus (>35 minutes - Third-line)

• ITU admission
• Rapid sequence induction and intubation
• General anaesthesia: IV thiopental (3-5 mg/kg bolus then 3-5 mg/kg/hr), propofol (1-2 mg/kg bolus then 2-10 mg/kg/hr), or midazolam infusion (0.1-0.3 mg/kg bolus then 0.05-0.4 mg/kg/hr)
• Continuous EEG monitoring: target burst suppression for 24-48 hours
• Wean anaesthesia gradually after 24-48 hours: reintroduce if seizures recur

Super-refractory SE (>24 hours despite anaesthesia)

• Ketamine, immunotherapy (if autoimmune), ketogenic diet, hypothermia

Referral Criteria

• All status epilepticus: emergency management + neurology input
• RSE: ITU and neurology
• New-onset refractory SE (NORSE): investigate for autoimmune encephalitis

Mortality for convulsive SE: 10-20%. Mortality increases with: duration of SE, age, underlying aetiology (acute symptomatic worst), and need for anaesthesia. RSE mortality: ~30-50%. NCSE mortality: ~20-30%. Morbidity: ~10-20% of survivors develop new neurological deficit. Early treatment is key - mortality and morbidity increase sharply after 30 minutes of continuous seizure activity. Known epileptics with SE from medication non-compliance have better outcomes than acute symptomatic SE.

Status Epilepticus Treatment Protocol

Causes of Status Epilepticus

Key Facts

Febrile seizures are the most common seizure type in childhood. Parents should be reassured that simple febrile seizures are benign, do not cause brain damage, and have an excellent prognosis. The main clinical challenge is distinguishing febrile seizures from seizures caused by meningitis/encephalitis.

Epidemiology

Prevalence 2-5% of all children (higher in some populations - up to 8% in Japan). Peak incidence at 18 months. M:F 1.5:1. Strong genetic component - risk is 10-20% if first-degree relative affected. Most children have only one febrile seizure; ~30% have recurrence.

Aetiology

• Seizure occurs in the context of fever (≥38°C) from any cause (usually viral URTI, otitis media, UTI, roseola/HHV-6)
• NOT caused by CNS infection (meningitis/encephalitis must be excluded)
• Genetic predisposition: polygenic; FEB1-FEB8 loci identified; SCN1A mutations associated with severe forms
• The rapidly rising temperature rather than the absolute temperature is thought to be the key trigger

Pathophysiology

The immature brain (6 months-5 years) has a lower seizure threshold. Fever lowers this threshold further through: (1) enhanced neuronal excitability (temperature-dependent ion channel effects), (2) cytokine release (IL-1β), (3) altered GABA-A receptor function at elevated temperatures. The susceptibility resolves with brain maturation, hence the age-limited nature.

Simple Febrile Seizure (80%)

• Generalised tonic-clonic seizure
• Duration <15 minutes (usually <5 minutes)
• Single episode within 24-hour period
• No focal features
• Complete recovery within 1 hour
• Child developmentally normal

Complex Febrile Seizure (20%)

• Focal onset or features (one-sided jerking, eye deviation)
• Duration >15 minutes
• Multiple seizures within 24 hours
• Incomplete recovery within 1 hour
• Post-ictal neurological deficit (Todd's paresis)

Febrile Status Epilepticus

• Febrile seizure lasting >30 minutes (or >5 minutes by operational definition)
• Treat as per status epilepticus protocol

Red Flags (Exclude Meningitis/Encephalitis)

• Prolonged post-ictal state (>1 hour)
• Petechial/purpuric rash (meningococcal disease)
• Bulging fontanelle (infant - raised ICP)
• Neck stiffness (unreliable in <18 months)
• Persistent irritability/drowsiness after seizure resolves
• Complex features in child <18 months (low threshold for LP)

Simple Febrile Seizure

• No routine investigations needed (NICE CG160)
• Identify source of fever: clinical examination (ENT, urine dip, CXR if indicated)
• No EEG, no neuroimaging required for simple febrile seizures

Complex Febrile Seizure

• Bloods: FBC, CRP, U&Es, glucose, calcium, blood cultures (if unwell)
• Urine: MC&S (UTI is common occult source)
• LP: consider if <18 months with complex features (meningism unreliable); MUST perform LP if clinical suspicion of meningitis/encephalitis at any age
• EEG: not routinely indicated; consider if recurrent complex febrile seizures or concern for epilepsy
• MRI brain: consider if focal seizure, persistent neurological deficit, or developmental concerns

When to Perform LP (NICE CG160)

• Signs of meningitis/encephalitis at any age
• Child <18 months with complex febrile seizure
• Incomplete immunisation against Hib/meningococcus/pneumococcus
• Previously treated with antibiotics (may mask meningitis signs)

Acute Management

• Most febrile seizures stop spontaneously within 5 minutes - no intervention needed
• If seizure >5 minutes: buccal midazolam 0.3 mg/kg (or rectal diazepam 0.5 mg/kg) - parents of children with recurrent febrile seizures can be prescribed rescue midazolam
• Manage fever: paracetamol 15 mg/kg QDS or ibuprofen 5-10 mg/kg TDS (for comfort, NOT to prevent febrile seizures - antipyretics do NOT prevent recurrence)
• Identify and treat source of infection: antibiotics if bacterial infection identified

Parental Education and Reassurance

• Febrile seizures are common and benign (simple type)
• No brain damage occurs from simple febrile seizures
• Not epilepsy (though small increased risk)
• Recurrence: ~30% chance of another febrile seizure; does not mean child will develop epilepsy
• What to do if seizure occurs: stay calm, place child on side, do not restrain, note time, call 999 if >5 minutes

Prophylaxis

• Regular antipyretics do NOT prevent febrile seizures (multiple RCTs)
• Intermittent benzodiazepine prophylaxis: NOT routinely recommended; may be considered in exceptional circumstances (very frequent or prolonged febrile seizures) - oral clobazam during febrile illnesses
• Continuous AED prophylaxis: NOT recommended for febrile seizures (risks outweigh benefits)

Referral Criteria

• Paediatric assessment: all first febrile seizures should be assessed by a doctor (NICE CG160)
• Paediatric neurology: recurrent complex febrile seizures, developmental concerns, febrile status epilepticus, family history of epilepsy
• Admit: first febrile seizure in child <18 months, complex febrile seizure, febrile status epilepticus, unwell child, diagnostic uncertainty, social concerns

Simple febrile seizures: excellent prognosis. No long-term cognitive or developmental effects. Recurrence risk ~30% after first episode (higher if age <18 months, family history, low temperature threshold, short duration of fever before seizure). Epilepsy risk after simple febrile seizure: 1-2% (similar to general population). Complex febrile seizures: higher epilepsy risk (4-12%), particularly with focal features or prolonged duration. Febrile status epilepticus: associated with mesial temporal sclerosis and temporal lobe epilepsy (FEBSTAT study).

Simple vs Complex Febrile Seizure

Recurrence Risk Factors

Key Facts

MS is a chronic immune-mediated demyelinating disease of the CNS. Early diagnosis and initiation of disease-modifying therapy can significantly reduce relapse rate and delay disability accumulation. The approach to MS has been revolutionised by highly effective DMTs.

Epidemiology

UK prevalence ~130 per 100,000 (~130,000 people affected). Incidence ~7 per 100,000 per year. F:M 3:1. Mean age of onset 20-40 years. Higher prevalence with increasing distance from the equator (vitamin D hypothesis). Scotland has one of the highest prevalences globally. Genetic susceptibility: HLA-DRB1*15:01; concordance in monozygotic twins ~25-30%.

Aetiology

Multifactorial: genetic susceptibility (HLA-DRB1*15:01) + environmental triggers including EBV infection (virtually 100% of MS patients are EBV seropositive), low vitamin D, smoking, adolescent obesity. EBV is increasingly considered a necessary (but not sufficient) cause of MS.

Pathophysiology

Common Presentations

• Optic neuritis: unilateral painful visual loss (pain on eye movement); relative afferent pupillary defect (RAPD); colour desaturation; 50% of ON patients develop MS
• Transverse myelitis: sensory level, limb weakness/spasticity, bladder dysfunction; Lhermitte sign (electric shock down spine on neck flexion)
• Brainstem/cerebellar: diplopia (INO - internuclear ophthalmoplegia), vertigo, ataxia, nystagmus, trigeminal neuralgia (young patient)
• Sensory: paraesthesiae, numbness, band-like sensations
• Motor: spasticity, weakness, fatigue

MS Subtypes

• RRMS (85%): episodes of neurological dysfunction (relapses) followed by partial/complete recovery; relapses last days-weeks
• SPMS: follows RRMS; progressive disability accumulation ± superimposed relapses
• PPMS (10-15%): progressive disability from onset without distinct relapses; older onset, equal sex ratio, spinal cord predominant

Red Flags

• Rapidly progressive course (consider NMO, ADEM, CNS lymphoma)
• Bilateral optic neuritis simultaneously (NMO rather than MS)
• Longitudinally extensive transverse myelitis (≥3 segments - NMO)
• Peripheral nervous system involvement (NOT MS - consider NMO, CIDP)

MRI

• MRI brain + spine with gadolinium: essential; demonstrates DIS and DIT
  • T2/FLAIR: hyperintense white matter lesions in periventricular (Dawson fingers), juxtacortical, infratentorial, and spinal cord locations
  • Gadolinium enhancement: active (new) lesions enhance for ~4-6 weeks
  • DIS: ≥1 T2 lesion in ≥2 of 4 typical areas
  • DIT: simultaneous enhancing and non-enhancing lesions on single scan, OR new T2/enhancing lesion on follow-up MRI

CSF

• Lumbar puncture: oligoclonal bands (OCBs) in CSF but not matched in serum - present in >95% of MS; can substitute for DIT in McDonald criteria
• Mildly raised lymphocytes, raised IgG index

Bloods

• AQP4 and MOG antibodies: exclude NMOSD/MOGAD
• B12, folate: exclude deficiency
• HIV, syphilis serology: exclude mimics
• ANA, dsDNA, ACE: exclude SLE, sarcoidosis
• NMO-IgG (AQP4-Ab): essential to exclude NMO

Other

• Visual evoked potentials (VEPs): delayed P100 latency in optic neuritis (even subclinical)
• OCT (optical coherence tomography): retinal nerve fibre layer thinning - marker of axonal loss

Acute Relapse

• IV methylprednisolone 1 g daily × 3-5 days (oral methylprednisolone 500 mg daily × 5 days if IV not possible)
• Shortens relapse duration but does NOT affect long-term disability
• Plasma exchange for severe relapses refractory to steroids

Disease-Modifying Therapies (NICE NG220)

RRMS - Moderate efficacy (first-line):

• Dimethyl fumarate 240 mg BD (DEFINE/CONFIRM trials); side effects: flushing, GI, lymphopenia (PML risk if prolonged lymphopenia)
• Teriflunomide 14 mg OD (TEMSO trial); teratogenic - Pregnancy Prevention Programme
• Interferon-β (Avonex, Rebif, Betaferon); flu-like symptoms, injection site reactions
• Glatiramer acetate 20 mg daily or 40 mg TIW SC

RRMS - High efficacy (escalation or first-line for active disease):

• Natalizumab 300 mg IV monthly (AFFIRM trial); anti-α4-integrin; risk of PML (JC virus - check JCV antibody index; PML risk ~1 in 250 if JCV+ >2 years)
• Ocrelizumab 600 mg IV 6-monthly (OPERA I/II trials); anti-CD20; also licensed for PPMS (ORATORIO trial)
• Alemtuzumab IV (CARE-MS I/II); anti-CD52; highly effective but risk of secondary autoimmunity (thyroid 30%, ITP 1-2%, Goodpasture - requires 4-year monitoring)
• Cladribine 3.5 mg/kg total over 2 years (CLARITY trial)
• Ofatumumab 20 mg SC monthly (ASCLEPIOS trials); anti-CD20

PPMS:

• Ocrelizumab (ORATORIO trial) - only DMT with evidence in PPMS; reduces disability progression

SPMS:

• Siponimod 2 mg OD (EXPAND trial) - for active SPMS

Symptom Management

• Spasticity: baclofen 5-100 mg/day, gabapentin, tizanidine, Sativex (nabiximols - NICE)
• Fatigue: amantadine 100 mg BD, CBT, exercise
• Neuropathic pain: amitriptyline 10-75 mg ON, gabapentin 300-3600 mg/day, pregabalin
• Bladder: intermittent self-catheterisation, oxybutynin 2.5-5 mg BD-TDS, mirabegron
• Depression: SSRIs

Referral Criteria

• All suspected MS: neurology (seen within 6 weeks - NICE NG220)
• DMT initiation and monitoring by MS specialist
• MDT: MS nurse, physiotherapy, occupational therapy, continence, psychology

Highly variable. RRMS: ~50% convert to SPMS within 15-20 years (less with modern DMTs). Life expectancy reduced by ~7-10 years. PPMS has worse prognosis (progressive from onset). Poor prognostic factors: male sex, older onset, motor/cerebellar presentation, incomplete relapse recovery, high lesion load, brain atrophy. Good prognosis: young onset, sensory/optic neuritis presentation, female, low lesion load. Modern DMTs have significantly improved outcomes - early high-efficacy treatment may change the natural history.

McDonald Criteria 2017 (Simplified)

MS Subtypes Comparison

Key Facts

NMOSD is a severe autoimmune inflammatory CNS disorder that must be distinguished from MS because treatment strategies differ fundamentally. AQP4-IgG seropositivity is the hallmark. Early immunosuppression reduces relapse rate and disability.

Epidemiology

Prevalence ~1-5 per 100,000. More common in non-Caucasian populations (African, Asian, Hispanic). F:M 9:1 (for AQP4+ disease). Mean age of onset 30-40 years (older than MS). Relapsing course in >90% of AQP4+ patients.

Aetiology

• AQP4-IgG seropositive NMOSD (~80%): pathogenic IgG1 antibodies against aquaporin-4 (most abundant water channel in CNS - expressed on astrocyte foot processes, particularly at optic nerves, spinal cord, and area postrema)
• AQP4-IgG seronegative NMOSD (~20%): some have MOG-IgG antibodies (MOGAD - now considered separate disease); others remain seronegative
• Associated autoimmune conditions: SLE, Sjögren syndrome, myasthenia gravis, autoimmune thyroiditis

Pathophysiology

Core Clinical Features

• Optic neuritis: often bilateral or rapidly sequential; severe visual loss; poor recovery compared to MS-related ON
• Longitudinally extensive transverse myelitis (LETM): ≥3 vertebral segments of T2 lesion on MRI; severe paraparesis/tetraparesis, sensory level, bladder dysfunction; often central cord
• Area postrema syndrome: intractable nausea, vomiting, hiccups (may be presenting feature - days to weeks)
• Brainstem syndrome: diplopia, facial palsy, vertigo
• Diencephalic syndrome: narcolepsy, SIADH
• Cerebral syndrome: encephalopathy (rare)

Key Differences from MS

• More severe relapses with poorer recovery
• Bilateral/severe optic neuritis (MS usually unilateral, milder)
• LETM ≥3 segments (MS usually <2 segments)
• Brain MRI often normal or atypical for MS (periependymal/hypothalamic lesions)
• Relapsing course without progressive phase

Red Flags

• Bilateral severe optic neuritis (NMOSD until proven otherwise)
• LETM on MRI (≥3 segments)
• Intractable hiccups/vomiting (area postrema)
• Worsening on interferon-β or other MS DMTs

Serology

• AQP4-IgG (NMO-IgG): cell-based assay (best sensitivity ~80% and specificity >99%); MUST be tested in all suspected NMOSD
• MOG-IgG: if AQP4 negative; cell-based assay
• ANA, dsDNA, ENA, complement: associated autoimmune conditions

MRI

• MRI brain: often normal or shows atypical lesions for MS (periependymal, hypothalamic, area postrema); does NOT typically show periventricular Dawson fingers
• MRI spine: LETM (≥3 vertebral segments of T2 hyperintensity); central cord predominance; bright spotty lesions
• MRI orbits (fat-suppressed): optic nerve enhancement (often posterior, long segment, bilateral)

CSF

• OCBs: often absent (present in only ~20% of NMOSD vs >95% in MS - key distinguishing feature)
• Pleocytosis: neutrophilic (unusual in MS where lymphocytic)
• Elevated protein: more common than in MS
• GFAP levels: raised (astrocyte damage marker)

Other

• VEPs: delayed/absent (severe optic nerve damage)
• OCT: significant RNFL thinning (often more severe than MS)

Acute Relapse

• IV methylprednisolone 1 g daily × 5 days: first-line
• Plasma exchange (PLEX): 5-7 exchanges; use early if poor response to steroids or severe attack (especially LETM or severe ON)
• More aggressive treatment than MS relapses - NMOSD attacks cause more permanent damage

Relapse Prevention (Maintenance Immunosuppression)

• First-line: rituximab 1 g IV × 2 doses (2 weeks apart), then 500 mg-1 g every 6 months; anti-CD20 B cell depletion; widely used; monitor CD19 count
• Eculizumab 900-1200 mg IV every 2 weeks (anti-C5 complement; PREVENT trial; NICE TA853); highly effective for AQP4+ NMOSD; risk of meningococcal infection - must vaccinate
• Satralizumab 120 mg SC monthly × 3 then every 4 weeks (anti-IL-6R; SAkuraStar/SAkuraSky trials)
• Inebilizumab 300 mg IV every 6 months (anti-CD19; N-MOmentum trial)
• Older agents: azathioprine 2.5 mg/kg/day, mycophenolate mofetil 1-3 g/day (used where biologics unavailable)
• DO NOT USE MS DMTs: interferon-β, natalizumab, fingolimod - can worsen NMOSD

Symptom Management

• Spasticity, pain, bladder - as per MS
• Rehabilitation: physiotherapy, occupational therapy
• Low-vision aids for severe visual loss

Referral Criteria

• All suspected NMOSD: urgent neurology (specialist NMO centre)
• AQP4 testing in all atypical demyelinating presentations
• MDT management at specialist centre

AQP4+ NMOSD: relapsing course in >90%; each relapse can cause significant irreversible disability; 5-year mortality ~20-30% without treatment (mainly respiratory failure from cervical myelitis). With modern immunosuppression (rituximab, eculizumab), outcomes have greatly improved - annualised relapse rate reduced by >90%. MOGAD: generally better prognosis; more likely to be monophasic; better relapse recovery. Seronegative NMOSD: variable prognosis.

NMOSD vs MS

Key NMOSD Trials

Key Facts

PD is a clinical diagnosis based on the presence of bradykinesia plus at least one additional motor feature. Treatment is symptomatic - levodopa remains the gold standard. Management of motor complications and non-motor symptoms is increasingly important as the disease progresses.

Epidemiology

Prevalence ~2 per 1,000 (1% of over-60s); ~150,000 people affected in UK. Incidence ~15-20 per 100,000 per year. M:F 1.5:1. Mean age of onset ~60 years. Young-onset PD (<40 years) accounts for ~5%. Incidence rising (aging population).

Aetiology

• Idiopathic (most common): multifactorial - genetic susceptibility + environmental factors
• Genetic: LRRK2 (commonest genetic cause - autosomal dominant), GBA (glucocerebrosidase - major risk factor), PARK2/Parkin, PINK1, SNCA (α-synuclein)
• Environmental: pesticide exposure, rural living, head trauma; protective factors: smoking (paradoxical), caffeine

Pathophysiology

Motor Features

• Bradykinesia: slowness of movement + progressive reduction in speed/amplitude with repetition (essential for diagnosis); difficulty with fine movements (writing - micrographia, buttoning)
• Rest tremor: 4-6 Hz, pill-rolling; present at rest, reduced with action; often asymmetric onset; affects hands/arms first
• Rigidity: lead-pipe rigidity (uniform throughout range); cogwheel rigidity (lead-pipe + superimposed tremor)
• Postural instability: late feature; impaired postural reflexes → falls (pull test positive)
• Gait: shuffling, reduced arm swing, festination (involuntary acceleration), freezing of gait
• Asymmetric onset: characteristically unilateral initially, progressing to bilateral

Non-Motor Features

• Neuropsychiatric: depression (40%), anxiety, apathy, PD dementia (PDD - 50% at 10 years), visual hallucinations, psychosis
• Autonomic: constipation (earliest non-motor symptom), orthostatic hypotension, urinary frequency/urgency, erectile dysfunction, sweating
• Sleep: REM sleep behaviour disorder (prodromal - precedes motor symptoms by years), insomnia, excessive daytime sleepiness
• Sensory: anosmia/hyposmia (early - often prodromal), pain
• Other: fatigue, micrographia, hypomimia (mask-like face), hypophonia (quiet speech)

Red Flags (Suggest Alternative Diagnosis)

• Symmetric onset (MSA, PSP)
• Rapid progression (MSA, PSP, CBD)
• Poor/absent response to levodopa (MSA, PSP)
• Early falls (PSP)
• Prominent autonomic failure (MSA)
• Vertical gaze palsy (PSP)
• Early severe dementia (DLB)
• Cerebellar signs (MSA-C)

Clinical Diagnosis

• Diagnosis is primarily clinical (NICE NG71): bradykinesia + ≥1 of rest tremor, rigidity, postural instability
• Response to levodopa supports diagnosis (but not diagnostic)

Imaging

• DaTSCAN (¹²³I-FP-CIT SPECT): dopamine transporter imaging; reduced uptake in striatum confirms nigrostriatal degeneration; useful to distinguish PD from essential tremor, drug-induced parkinsonism, or psychogenic tremor (DaTSCAN normal in these conditions)
• MRI brain: usually normal in PD; helps exclude vascular parkinsonism, PSP (hummingbird sign), MSA (hot cross bun sign), NPH

Bloods

• Copper/caeruloplasmin: exclude Wilson disease in young-onset (<50)
• TFTs: exclude hypothyroidism

Other

• Olfactory testing: hyposmia supports PD (reduced in ~90%)
• Genetic testing: consider if young-onset (<40) or strong family history (LRRK2, GBA, Parkin, PINK1)

Pharmacological (NICE NG71)

Initial Treatment (choice depends on patient preference, symptoms, lifestyle):

• Levodopa (co-beneldopa 62.5-250 mg TDS or co-careldopa 62.5-250 mg TDS): most effective symptomatic therapy; start low, titrate; always given with dopa-decarboxylase inhibitor (benserazide or carbidopa) to reduce peripheral side effects
• Dopamine agonists: ropinirole 0.25-24 mg/day, pramipexole 0.088-3.3 mg/day, rotigotine patch 2-16 mg/24h; less motor complications than levodopa but less effective; side effects: impulse control disorders (gambling, hypersexuality, compulsive spending - warn patient), somnolence, hallucinations
• MAO-B inhibitors: rasagiline 1 mg OD, selegiline 5-10 mg OD, safinamide 50-100 mg OD; mild symptomatic benefit; may delay need for levodopa

Motor Complications Management:

• Wearing-off: increase levodopa frequency, add COMT inhibitor (entacapone 200 mg with each levodopa dose - Stalevo combination), add MAO-B inhibitor, add dopamine agonist
• Dyskinesias: reduce individual levodopa doses, add amantadine 100 mg BD-TDS
• On-off fluctuations: as above + consider advanced therapies

Advanced Therapies (specialist centre):

• Apomorphine SC infusion: continuous dopamine agonist; for severe motor fluctuations
• Levodopa-carbidopa intestinal gel (LCIG/Duodopa): continuous jejunal infusion via PEG-J; reduces off-time
• Deep brain stimulation (DBS): bilateral subthalamic nucleus (STN) or globus pallidus interna (GPi); for motor fluctuations/dyskinesias refractory to medical therapy; NICE IPG19

Non-Pharmacological

• MDT approach: PD nurse, physiotherapy (gait, balance, falls prevention), occupational therapy, speech and language therapy (LSVT LOUD for hypophonia), dietitian
• Exercise: strong evidence for benefit; tai chi, dance, boxing classes

Non-Motor Symptom Management

• Depression: SSRIs (citalopram, sertraline); avoid TCAs in elderly
• Dementia (PDD): rivastigmine (NICE TA); only cholinesterase inhibitor licensed for PDD
• Psychosis/hallucinations: reduce/stop anticholinergics and dopamine agonists first; quetiapine 12.5-100 mg (first-line - lowest EPS risk); clozapine (if refractory); AVOID typical antipsychotics (worsen parkinsonism)
• Orthostatic hypotension: fludrocortisone 100-300 μg OD, midodrine 2.5-10 mg TDS
• Constipation: macrogol (Movicol), adequate hydration, exercise
• RBD: clonazepam 0.25-2 mg ON, melatonin 2-6 mg ON

Referral Criteria

• All suspected PD: specialist with expertise in movement disorders (NICE NG71) - do not initiate treatment in primary care
• Advanced therapies: tertiary movement disorder centre

PD is progressive; rate varies between individuals. Mean duration from diagnosis to death ~15 years. Dementia develops in ~50% at 10 years (strongest predictor of nursing home admission). Falls and aspiration pneumonia are major causes of morbidity/mortality in advanced disease. Levodopa motor complications affect ~50% at 5 years. Quality of life is significantly affected by non-motor symptoms. DBS and advanced therapies can significantly improve quality of life in selected patients. No neuroprotective therapy has been proven to date.

PD vs Parkinson-Plus Syndromes

Hoehn and Yahr Staging

Key Facts

Essential tremor (ET) is the most common movement disorder, often underdiagnosed and undertreated. It is a clinical diagnosis requiring exclusion of other causes of tremor. Despite its name, ET can cause significant functional impairment and social embarrassment.

Epidemiology

Prevalence ~1% overall; ~5% in over-60s. Bimodal age of onset (peak in 2nd-3rd decade and 6th-7th decade). Positive family history in ~50% (autosomal dominant with variable penetrance). Equal sex distribution.

Aetiology

• Genetic: autosomal dominant with variable penetrance; multiple loci identified (ETM1, ETM2, LINGO1 gene polymorphism)
• Sporadic: cases without family history - possibly polygenic or de novo
• Exact genetic basis remains incompletely understood

Pathophysiology

Tremor Characteristics

• Action tremor: present during voluntary movement (e.g., writing, drinking, eating)
• Postural tremor: present when maintaining posture against gravity (e.g., arms outstretched)
• Frequency: 4-12 Hz (typically 6-8 Hz)
• Bilateral (may be asymmetric but almost always bilateral)
• Progressive: slowly worsens over years/decades

Distribution

• Hands/arms: most common (95%); interferes with writing (large, irregular - vs micrographia in PD), drinking, eating
• Head: titubation (yes-yes or no-no nodding) - ~30%
• Voice: tremulous speech - ~20%
• Legs: uncommon

Associated Features

• Improves with alcohol (ethanol)
• Worsens with anxiety, caffeine, fatigue, cold
• No bradykinesia, no rigidity, no postural instability
• Gait usually normal (mild tandem gait difficulty in some)

Red Flags (Suggest Alternative Diagnosis)

• Rest tremor (PD)
• Bradykinesia or rigidity (PD)
• Unilateral tremor that remains unilateral (PD)
• Acute onset (drug/toxin, psychogenic)
• Associated neurological signs (cerebellar signs, dystonia, neuropathy)

Clinical Diagnosis

• Diagnosis is clinical: bilateral action/postural tremor ± head/voice tremor; no bradykinesia/rigidity; family history supports
• No specific blood test or imaging required for typical presentation

Investigations (if Diagnostic Uncertainty)

• DaTSCAN: NORMAL in ET (abnormal in PD) - key differentiating investigation
• TFTs: exclude hyperthyroidism (enhanced physiological tremor)
• U&Es, LFTs: metabolic causes
• Drug review: valproate, lithium, amiodarone, salbutamol, SSRIs
• MRI brain: if cerebellar signs or atypical features
• EMG/accelerometry: research/specialist use - characterise tremor frequency and pattern

Non-pharmacological

• Reassurance: ET is not PD; ET is benign in terms of life expectancy
• Lifestyle: reduce caffeine, manage stress/anxiety, adequate sleep
• Weighted utensils/adaptive devices: practical aids for eating/drinking
• Occupational therapy: functional strategies

Pharmacological

• First-line: propranolol 40-320 mg/day (long-acting SR formulation preferred - 80-160 mg OD; tremor reduction 50-70%; contraindicated in asthma, heart block, severe bradycardia)
• Alternative first-line: primidone 25-750 mg/day (start very low - 12.5-25 mg ON; titrate slowly; metabolised to phenobarbitone; sedation and dizziness common initially)
• Second-line: topiramate 25-400 mg/day (weight loss, cognitive side effects), gabapentin 300-2400 mg/day
• Others: alprazolam (short-term), botulinum toxin (head/voice tremor)

Surgical (Refractory)

• Deep brain stimulation (DBS): VIM (ventral intermediate nucleus) thalamic DBS; for severe, medication-refractory ET causing significant disability; NICE IPG - 60-80% tremor reduction
• MRI-guided focused ultrasound (FUS) thalamotomy: non-invasive alternative to DBS; unilateral only; NICE IPG

Referral Criteria

• Neurology: diagnostic uncertainty, poor treatment response, consideration of DBS
• Functional impact: occupational therapy assessment

ET is a slowly progressive condition. Tremor amplitude typically increases over decades. Frequency may decrease with age. ET does NOT reduce life expectancy. Functional impairment is common - many patients have difficulty with writing, eating, drinking, and fine motor tasks. Social embarrassment is significant. ~50% of patients require treatment. Propranolol and primidone provide good symptomatic relief in most. DBS is highly effective for refractory cases. Some epidemiological studies suggest a modestly increased risk of dementia and PD in ET patients, but this remains debated.

Essential Tremor vs Parkinson Disease Tremor

Key Facts

Huntington disease (HD) is a devastating progressive neurodegenerative condition with autosomal dominant inheritance. Diagnosis carries profound implications for the patient and family. Predictive genetic testing is available but requires careful genetic counselling.

Epidemiology

Prevalence ~12 per 100,000 in UK/Europe (higher than previously estimated). Incidence ~0.5-1 per 100,000 per year. Mean age of onset 35-45 years. Juvenile HD (<20 years) accounts for ~5% (more rapid progression, rigidity > chorea). Equal sex distribution.

Aetiology

Expansion of CAG trinucleotide repeat in exon 1 of HTT gene (chromosome 4p16.3). Normal: <26 repeats. Full penetrance: ≥40 repeats. The number of CAG repeats correlates inversely with age of onset. Anticipation: repeat length tends to increase with paternal transmission (spermatogenesis - meiotic instability), leading to earlier onset in successive generations.

Pathophysiology

Motor Features

• Chorea: involuntary, irregular, non-repetitive, flowing movements; most characteristic feature; affects face, trunk, and limbs; may be subtle early (fidgeting, clumsiness)
• Dystonia: more prominent as disease progresses
• Rigidity and akinesia: late features (replace chorea as disease advances - "Westphal variant" in juvenile HD)
• Oculomotor abnormalities: slowed saccades (early sign), gaze impersistence
• Dysarthria and dysphagia: progressive
• Gait disturbance: wide-based, dance-like

Cognitive Features

• Executive dysfunction (early): planning, multitasking, problem-solving
• Progressive subcortical dementia: memory, attention, concentration
• Eventual severe dementia

Psychiatric Features (Often Precede Motor Symptoms)

• Depression (40-50% - commonest psychiatric feature; high suicide risk)
• Irritability and aggression
• Apathy
• Psychosis (hallucinations, paranoid delusions - ~10%)
• OCD-like behaviours

Red Flags

• Chorea + cognitive decline + psychiatric symptoms + positive family history
• Juvenile onset: rigidity > chorea, seizures, rapid progression
• Suicide risk: 4× general population (especially around diagnosis and loss of independence)

Genetic Testing

• HTT gene CAG repeat count: diagnostic; ≥40 repeats = fully penetrant; 36-39 = reduced penetrance; 27-35 = intermediate (may expand in next generation)
• Predictive testing: for at-risk individuals (offspring of affected parent - 50% risk); requires genetic counselling (minimum 2 sessions), psychological assessment, and informed consent; performed in specialist genetics centres

Imaging

• MRI brain: caudate nucleus atrophy (loss of convexity of caudate heads → ex vacuo dilatation of frontal horns of lateral ventricles - "boxcar" ventricles); cortical atrophy (frontal predominant)
• CT brain: may show caudate atrophy but less sensitive than MRI

Bloods

• Copper, caeruloplasmin: exclude Wilson disease in young-onset chorea
• Blood film: acanthocytes (neuroacanthocytosis)
• TFTs: thyrotoxicosis (chorea)
• Autoantibodies: SLE, antiphospholipid syndrome

Pharmacological (Symptomatic Only)

• Chorea: tetrabenazine 12.5-100 mg/day (vesicular monoamine transporter 2 (VMAT2) inhibitor - depletes dopamine; main side effects: depression, sedation, parkinsonism); NICE recommendation
  • Alternative: sulpiride, olanzapine, risperidone (if tetrabenazine not tolerated)
  • Deutetrabenazine (modified formulation - fewer side effects; not yet widely available in UK)
• Depression: SSRIs (citalopram, sertraline) - first-line; mirtazapine if insomnia/weight loss; monitor suicide risk
• Psychosis/aggression: olanzapine, risperidone, quetiapine (low-dose atypical antipsychotics)
• OCD features: SSRIs (fluoxetine, sertraline)
• Insomnia: zopiclone, melatonin

Non-pharmacological

• MDT: neurology, psychiatry, genetic counselling, physiotherapy, occupational therapy, speech and language therapy, dietitian, social work, palliative care
• Physiotherapy: maintain mobility, prevent falls, stretching (contractures)
• Speech and language therapy: swallowing assessment (aspiration risk), communication aids
• Dietitian: weight loss is common (hypermetabolism + dysphagia); high-calorie diet, PEG feeding in advanced disease
• Psychological support: for patient and family (carers)

Genetic Counselling

• All patients and at-risk family members should be offered genetic counselling
• Predictive testing protocol: ≥2 counselling sessions, psychological assessment, informed consent, no obligation to test
• Prenatal testing and pre-implantation genetic diagnosis (PGD) available

Palliative Care

• Early involvement recommended; advance care planning
• End-of-life: aspiration pneumonia, cachexia, falls are common causes of death

Referral Criteria

• All suspected HD: specialist neurogenetics service
• Psychiatric input: depression, psychosis, suicide risk
• Palliative care: early referral for symptom management and advance planning

Mean survival 15-20 years from symptom onset. Juvenile HD has more rapid course (8-10 years). Death usually from aspiration pneumonia, cardiovascular disease, or suicide. Suicide risk is 4× general population (particularly around time of diagnosis, loss of driving, loss of independence). Chorea tends to peak then decline as rigidity/akinesia supervene. Cognitive and functional decline is relentless. There is no disease-modifying treatment (antisense oligonucleotides and gene-silencing therapies are in clinical trials - GENERATION-HD1 was discontinued but newer approaches continue).

CAG Repeat Classification

Trinucleotide Repeat Disorders (Comparison)

Key Facts

MND is a progressive, fatal neurodegenerative condition. Diagnosis is clinical, supported by EMG. Early MDT involvement and palliative care are essential. Riluzole offers modest survival benefit.

Epidemiology

Incidence ~2 per 100,000/year. Prevalence ~5-7 per 100,000. Mean age of onset 55-65 years. M:F 1.5:1. Lifetime risk ~1 in 300. ~90% sporadic; ~10% familial.

Aetiology

• Sporadic (~90%): cause unknown; multifactorial with environmental and genetic contributions
• Familial (~10%): C9orf72 hexanucleotide repeat expansion (commonest - ~40% of familial MND; also causes FTD), SOD1 mutations (~20% of familial), TARDBP (TDP-43), FUS
• Risk factors: increasing age, male sex, smoking, possible military service

Pathophysiology

Selective degeneration of motor neurones in the motor cortex (UMN), brainstem motor nuclei, and anterior horn cells of the spinal cord (LMN). TDP-43 protein inclusions found in >95% of sporadic ALS. Glutamate excitotoxicity (basis for riluzole - glutamate release inhibitor). Protein aggregation, oxidative stress, mitochondrial dysfunction, and neuroinflammation all contribute. Eye movements and sphincters are spared because Onuf's nucleus and oculomotor nuclei are resistant.

Typical Presentations

• Limb-onset ALS (~65%): asymmetric weakness/wasting of hand (split hand sign - thenar > hypothenar) or foot drop; mixed UMN + LMN signs
• Bulbar-onset ALS (~25%): dysarthria (slurred speech), dysphagia, tongue wasting/fasciculations; worse prognosis
• Respiratory onset (~5%): dyspnoea, orthopnoea, morning headaches from nocturnal hypoventilation

UMN Signs

• Spasticity, hyperreflexia, upgoing plantars, clonus, brisk jaw jerk, pseudobulbar affect (emotional lability)

LMN Signs

• Muscle wasting, weakness, fasciculations (visible twitching), hyporeflexia/areflexia, muscle cramps

Red Flags

• Sensory involvement → NOT MND (consider cervical myelopathy, CIDP)
• Eye movement abnormality → NOT typical MND
• Early sphincter involvement → NOT MND (consider spinal cord compression)
• Symmetric onset → atypical (consider Kennedy disease, SMA)
• Very slow progression (>5 years) → consider PLS, Kennedy disease

Bedside

• Clinical examination: mixed UMN + LMN signs in multiple regions
• FVC (forced vital capacity): baseline and serial monitoring (respiratory function)

Bloods

• CK: mildly raised in MND (usually <1000 IU/L)
• TFTs, glucose, B12, folate: exclude metabolic causes
• Anti-GM1 antibodies: exclude multifocal motor neuropathy
• Serum protein electrophoresis: exclude paraprotein
• Genetic testing: C9orf72, SOD1 if familial or FTD features

Imaging

• MRI brain + spine: exclude structural causes (cervical myelopathy, foramen magnum lesions); usually normal in MND

Special Tests

• EMG/nerve conduction studies (NCS): essential - shows widespread denervation (fibrillations, positive sharp waves, fasciculations) with preserved sensory nerves; Awaji criteria incorporate EMG findings
• Revised El Escorial criteria: clinical classification (definite, probable, possible MND) based on UMN + LMN signs in multiple body regions
• FVC and SNIP (sniff nasal inspiratory pressure): respiratory muscle strength

Pharmacological

• Riluzole 50 mg BD: only disease-modifying drug; glutamate release inhibitor; extends survival by ~2-3 months; NICE TA20; monitor LFTs
• No cure: all other treatments are symptomatic

Non-pharmacological

• MDT essential: neurology, respiratory, SALT, dietitian, OT, PT, palliative care, MND nurse specialist, social worker, psychology
• Nutrition: SALT assessment for swallowing; high-calorie supplements; PEG/RIG insertion when swallowing unsafe (insert early while FVC >50%)
• Respiratory: NIV (non-invasive ventilation - BiPAP) for respiratory failure; improves survival by ~7 months (NICE); monitor with serial FVC/SNIP; initiate when FVC <50% or symptoms
• Communication: speech aids, eye-tracking technology, letter boards
• Physiotherapy: maintain mobility, prevent contractures

Symptom Management

• Sialorrhoea: hyoscine patches, glycopyrronium 1-2 mg TDS, botulinum toxin to salivary glands
• Spasticity: baclofen 5-80 mg/day, tizanidine
• Cramps: quinine 200-300 mg ON (limited evidence)
• Pseudobulbar affect: amitriptyline 10-50 mg ON
• Pain: paracetamol, NSAIDs, neuropathic agents
• Depression/anxiety: SSRIs, counselling

Palliative Care

• Early referral; advance care planning (ADRT, preferred place of death)
• End-of-life: respiratory failure is usual cause of death; opioids + benzodiazepines for dyspnoea/distress

Referral Criteria

• All suspected MND: urgent neurology referral (within 4 weeks - NICE)
• MND Association key worker involvement from diagnosis

Median survival from symptom onset: 2-5 years. Bulbar-onset: worse prognosis (~2 years). Limb-onset: ~3-5 years. ~10% survive >10 years (especially PLS, younger onset). FVC decline is the strongest prognostic indicator. Respiratory failure is the usual cause of death. Riluzole extends survival by ~2-3 months. NIV extends survival by ~7 months. PEG feeding does not clearly extend survival but improves nutrition and quality of life. C9orf72 associated with concomitant FTD and shorter survival.

MND Subtypes

Revised El Escorial Criteria

Key Facts

SMA is the commonest genetic cause of infant death. Caused by deficiency of survival motor neurone (SMN) protein. The advent of disease-modifying therapies (nusinersen, gene therapy, risdiplam) has transformed the prognosis, particularly when given pre-symptomatically.

Epidemiology

Incidence ~1 in 10,000 live births. Carrier frequency ~1 in 40-50. SMA type 1 accounts for ~60% of cases. No sex predilection. Newborn screening increasingly being implemented (included in UK newborn screening pilot).

Aetiology

Homozygous deletion or mutation of SMN1 (survival motor neurone 1) gene on chromosome 5q13. SMN2 (paralogous gene) partially compensates but produces predominantly truncated, unstable protein (~10% full-length SMN). SMN2 copy number is the main disease modifier.

Pathophysiology

SMA Type 1 (Werdnig-Hoffmann Disease)

• Onset <6 months; severe hypotonia ("floppy baby"); never achieve sitting
• Tongue fasciculations (hallmark); absent deep tendon reflexes
• Paradoxical (diaphragmatic) breathing; bell-shaped chest
• Feeding difficulties; bulbar weakness
• Normal cognition; alert, bright eyes
• Death from respiratory failure by age 2 without treatment

SMA Type 2

• Onset 6-18 months; can sit independently but never walk
• Proximal weakness, tremor of fingers (polyminimyoclonus)
• Scoliosis, joint contractures
• Respiratory complications later; survival to adulthood

SMA Type 3 (Kugelberg-Welander Disease)

• Onset >18 months; can walk independently (may lose ability in teens/adulthood)
• Proximal weakness, waddling gait, Gower sign
• Near-normal lifespan

SMA Type 4

• Adult onset (>21 years); mildest; slowly progressive proximal weakness

Red Flags

• Floppy infant with tongue fasciculations and absent reflexes → SMA type 1
• Progressive proximal weakness in child with normal cognition

Genetic Testing

• SMN1 gene analysis: homozygous deletion of exon 7 (and usually exon 8) confirms diagnosis in ~95%; MLPA or qPCR
• SMN2 copy number: determines prognosis and guides treatment decisions
• Carrier testing: for family members; prenatal diagnosis available

Bloods

• CK: normal or mildly elevated (unlike muscular dystrophies where markedly raised)

Neurophysiology

• EMG: denervation pattern (fibrillations, positive sharp waves, large-amplitude polyphasic MUPs); normal sensory nerves
• NCS: reduced CMAP amplitudes; normal sensory conduction

Other

• Muscle biopsy: rarely needed now (genetic testing is diagnostic); shows grouped atrophy (neurogenic)
• Respiratory function: serial FVC, sleep study; essential for monitoring

Disease-Modifying Therapies

• Nusinersen (Spinraza): antisense oligonucleotide; increases SMN2 exon 7 inclusion → more functional SMN protein; intrathecal injection; loading doses then 4-monthly; ENDEAR trial (type 1), CHERISH trial (type 2); NICE TA588
• Onasemnogene abeparvovec (Zolgensma): AAV9-mediated gene therapy delivering functional SMN1; single IV infusion; most effective when given pre-symptomatically or early in type 1; NICE HST15
• Risdiplam (Evrysdi): oral SMN2 splicing modifier; daily oral liquid; FIREFISH (type 1) and SUNFISH (type 2/3) trials; NICE TA755

Supportive Care (MDT)

• Respiratory: NIV, cough assist devices, chest physiotherapy, proactive management of respiratory infections
• Nutrition: nasogastric or gastrostomy feeding in type 1/severe type 2
• Orthopaedic: scoliosis management (bracing, surgery), contracture prevention
• Physiotherapy: maintain function, prevent contractures
• Palliative care: especially type 1 if treatment not available or not chosen

Referral Criteria

• All suspected SMA: urgent paediatric neurology referral
• Specialist neuromuscular centre for treatment decisions

Type 1 without treatment: death by age 2. With nusinersen/gene therapy: significant improvement in motor milestones and survival. Type 2: survival to adulthood; progressive scoliosis and respiratory compromise. Type 3: near-normal lifespan; variable motor disability. Pre-symptomatic treatment (identified by newborn screening) gives the best outcomes - many treated infants achieve near-normal motor development. SMN2 copy number is the strongest predictor of natural history.

SMA Classification

Key SMA Trials

Key Facts

MG is the commonest disorder of the neuromuscular junction. Diagnosis requires demonstration of fatigable weakness and serological/electrophysiological confirmation. Thymoma must be excluded in all patients.

Epidemiology

Prevalence ~15-20 per 100,000. Bimodal: young women (20-30s, associated with thymic hyperplasia) and older men (60-70s, associated with thymoma). Prevalence rising (improved diagnosis, aging population).

Aetiology

• Anti-AChR antibodies (~85%): IgG1/3 targeting the nicotinic acetylcholine receptor at the postsynaptic NMJ → complement-mediated damage, receptor cross-linking/internalisation, and functional block
• Anti-MuSK antibodies (~5-10%): IgG4 targeting muscle-specific kinase; different clinical phenotype (bulbar predominant, facial/respiratory weakness, muscle atrophy)
• Seronegative (~5-10%): some have low-affinity AChR or anti-LRP4 antibodies
• Thymic pathology: thymoma (10-15%), thymic hyperplasia (65%); thymus contains AChR-like epitopes that may initiate autoimmunity

Pathophysiology

Ocular MG

• Ptosis (often asymmetric, may be alternating): worsens with sustained upgaze (Cogan lid twitch - overshoot on returning from downgaze)
• Diplopia: from extraocular muscle weakness (any pattern - mimics any cranial nerve palsy)
• Pupils NEVER affected (distinguishes from CN III palsy)

Generalised MG

• Bulbar: dysarthria, dysphagia, nasal speech, facial weakness (myasthenic snarl)
• Limb weakness: proximal > distal; arms > legs initially
• Respiratory: dyspnoea, orthopnoea → myasthenic crisis
• Neck flexion weakness (dropped head)

Myasthenic Crisis

• Respiratory failure requiring ventilatory support
• Triggered by infection, surgery, medication changes, stress
• Medical emergency - ITU admission

Red Flags

• Rapid respiratory deterioration
• FVC <20 mL/kg or declining
• Severe bulbar weakness (aspiration risk)
• New diagnosis with thymoma on CT

Serology

• Anti-AChR antibodies: positive in ~85% of generalised MG, ~50% of ocular MG; highly specific
• Anti-MuSK antibodies: if AChR negative; ~40% of AChR-seronegative patients
• Anti-LRP4 antibodies: research use; some seronegative patients

Neurophysiology

• Repetitive nerve stimulation (RNS): >10% decremental response at 3 Hz - diagnostic
• Single-fibre EMG (SFEMG): increased jitter; most sensitive test (~95% sensitivity); specialist investigation

Imaging

• CT thorax: MANDATORY in all MG patients to exclude thymoma
• MRI thorax: if CT equivocal

Bedside

• Ice pack test: place ice on closed eyelid for 2 minutes → improvement in ptosis supports MG (cooling improves NMJ transmission)
• FVC: serial monitoring in acute settings (myasthenic crisis)

Other

• TFTs: associated autoimmune thyroid disease
• ANA, anti-dsDNA: associated autoimmunity
• Edrophonium (Tensilon) test: largely abandoned in UK (cardiac risk); replaced by ice pack test

Symptomatic

• Pyridostigmine 30-120 mg QDS (anticholinesterase; first-line; side effects: cholinergic - abdominal cramps, diarrhoea, increased secretions, bradycardia)

Immunosuppression

• Prednisolone: start low (5-10 mg OD) and increase slowly (can initially worsen MG - "steroid dip"); maintenance 5-20 mg OD
• Azathioprine 2-3 mg/kg/day: steroid-sparing; check TPMT before starting; takes 3-6 months for effect
• Mycophenolate mofetil 1-3 g/day: if azathioprine not tolerated
• Rituximab: especially effective in MuSK-MG; increasingly used in refractory AChR-MG
• Eculizumab (anti-C5 complement; REGAIN trial; NICE TA992): for refractory generalised AChR-positive MG

Myasthenic Crisis

• IV immunoglobulin 0.4 g/kg/day × 5 days OR plasma exchange (5 exchanges over 10-14 days)
• ITU: monitor FVC closely; intubate if FVC <15-20 mL/kg or rapidly declining
• Identify and treat trigger (infection commonest)

Thymectomy

• Indicated if: thymoma (any age - curative intent) OR non-thymomatous generalised AChR+ MG in patients aged 18-65 (MGTX trial showed benefit)
• Not typically performed in MuSK-MG or seronegative MG

Drugs to AVOID

• Aminoglycosides, macrolides, fluoroquinolones, beta-blockers, D-penicillamine, phenytoin, quinine, magnesium sulphate

Referral Criteria

• All suspected MG: neurology (specialist neuromuscular centre)
• Thymoma: thoracic surgery
• Crisis: ITU

With modern immunotherapy, MG mortality is <5%. Ocular MG: ~50% generalise within 2 years; if remains ocular for 2 years, low risk of generalisation. Thymoma-associated MG: outcomes depend on tumour staging. Remission rates: ~10-20% achieve complete stable remission. Anti-MuSK MG: often more difficult to treat but responds well to rituximab. Most patients have a good quality of life with appropriate treatment.

Myasthenia Gravis Foundation of America (MGFA) Classification

MG vs Lambert-Eaton Syndrome

Key Facts

LEMS is a rare autoimmune channelopathy affecting presynaptic neuromuscular transmission. It is a paraneoplastic syndrome in ~60% (SCLC). Early cancer screening is essential.

Epidemiology

Rare: incidence ~0.5 per million/year. Prevalence ~2.5 per million. Paraneoplastic LEMS: older (>50 years), male predominance. Autoimmune LEMS: younger, female, associated with other autoimmune conditions.

Aetiology

• Paraneoplastic (~60%): SCLC expresses VGCC → immune response cross-reacts with NMJ; tumour usually found within 2 years of LEMS diagnosis
• Autoimmune (~40%): no underlying malignancy; associated with HLA-B8, other autoimmune diseases
• DELTA-P score: predicts cancer risk (Smoking, Age >50, Weight loss, Bulbar, Male, Karnofsky score)

Pathophysiology

Motor Features

• Proximal limb weakness: legs > arms; difficulty rising from chair, climbing stairs
• Weakness IMPROVES with repeated use (post-exercise facilitation - opposite of MG)
• Depressed/absent tendon reflexes: characteristic; reflexes may augment after brief exercise (post-tetanic potentiation)
• Waddling gait

Autonomic Features

• Dry mouth (commonest autonomic symptom), constipation, erectile dysfunction, orthostatic hypotension, urinary retention

Bulbar and Ocular Features

• Less prominent than MG; mild ptosis, diplopia, dysarthria, dysphagia may occur but NOT the presenting feature

Red Flags

• Older male smoker with proximal weakness → SCLC until proven otherwise
• Weight loss, cough, haemoptysis (underlying SCLC)
• Rapid progression of weakness

Serology

• Anti-VGCC antibodies (P/Q-type): positive in ~90% of LEMS; confirms diagnosis
• SOX1 antibodies: associated with paraneoplastic LEMS (SCLC)

Neurophysiology

• EMG: low compound muscle action potential (CMAP) amplitude at rest
• Repetitive nerve stimulation: decremental response at low-frequency (3 Hz) stimulation; >100% incremental response at high-frequency (20-50 Hz) stimulation or after 10 seconds of maximal voluntary contraction - diagnostic

Cancer Screening

• CT thorax (± CT abdomen/pelvis): SCLC screening; MANDATORY
• PET-CT: if CT negative but high clinical suspicion
• Repeat screening at 3-6 monthly intervals for 2 years if initially negative (cancer may present after LEMS)

Other

• DELTA-P score: risk stratification for underlying malignancy

Treat Underlying Malignancy

• If SCLC: chemotherapy ± radiotherapy (LEMS often improves with tumour treatment)

Symptomatic

• Pyridostigmine 30-120 mg QDS: adjunct (less effective than in MG)

Immunosuppression (Non-paraneoplastic)

• Prednisolone + azathioprine: as per MG
• IVIg or plasma exchange: for acute worsening
• Rituximab: for refractory cases

Referral Criteria

• All suspected LEMS: neurology + cancer screening
• Oncology if SCLC confirmed

Paraneoplastic LEMS: prognosis determined by underlying SCLC (5-year survival ~5-10% for SCLC). Interestingly, SCLC patients with LEMS may have better tumour outcomes than SCLC without LEMS (immune surveillance effect). Autoimmune LEMS: good prognosis with immunosuppression; chronic relapsing course. 3,4-DAP provides significant symptomatic improvement in >80% of patients.

LEMS vs Myasthenia Gravis Comparison

Key Facts

GBS is a medical emergency. Rapid identification, monitoring of respiratory function, and early treatment with IVIg or plasma exchange are essential. Most patients recover well but ~5% die and ~20% have significant residual disability.

Epidemiology

Incidence ~1-2 per 100,000/year. All ages (slight peak in young adults and elderly). M:F 1.5:1. Commonest cause of acute flaccid paralysis in developed countries.

Aetiology

Pathophysiology

• AIDP (~90% in UK): macrophage-mediated segmental demyelination of peripheral nerves and nerve roots; cell-mediated + humoral immunity; complement activation
• AMAN (acute motor axonal neuropathy): anti-GM1/GD1a antibodies target motor axons; more common in Asia, associated with Campylobacter; axonal degeneration
• AMSAN (acute motor and sensory axonal neuropathy): axonal variant affecting motor + sensory axons; worst prognosis
• Miller Fisher syndrome: anti-GQ1b antibodies; triad of ophthalmoplegia, ataxia, areflexia

Classic Presentation (AIDP)

• Preceding infection 1-4 weeks before (diarrhoea - Campylobacter; URTI - CMV, EBV)
• Ascending symmetrical weakness: starts in legs, progresses to arms, then bulbar/respiratory muscles
• Areflexia or hyporeflexia: early and universal
• Sensory symptoms: paraesthesiae, numbness (distal); pain in back/limbs is common (~70%)
• Progression to nadir within 4 weeks (usually 2 weeks)
• Autonomic dysfunction: tachycardia, bradycardia, labile BP, urinary retention, ileus

Miller Fisher Syndrome (~5%)

• Triad: ophthalmoplegia + ataxia + areflexia
• Anti-GQ1b antibodies (~95% positive)
• Usually good recovery

Red Flags

• Rapidly declining FVC → imminent respiratory failure
• Inability to lift head off pillow → severe weakness
• Bulbar weakness → aspiration risk
• Autonomic instability → cardiac arrhythmia risk
• Bladder involvement early → consider spinal cord pathology instead

Bedside

• FVC (forced vital capacity): serial monitoring Q4-6 hourly; intubate if <20 mL/kg, declining >30% from baseline, unable to cough effectively, or bulbar weakness with aspiration
• Observations: HR, BP (autonomic monitoring), SpO₂

CSF (Lumbar Puncture)

• Albuminocytological dissociation: raised protein (often >0.4 g/L) with normal white cell count (<10/μL)
• May be normal in first week - repeat if initially normal and clinical suspicion high
• Cell count >50/μL → consider alternative diagnosis (HIV, Lyme, sarcoid)

Neurophysiology

• NCS/EMG: AIDP - prolonged distal motor latencies, reduced conduction velocities, conduction block, prolonged/absent F-waves, temporal dispersion
• AMAN - reduced CMAP amplitudes with preserved conduction velocities, no conduction block
• May be normal in first few days

Bloods

• Anti-ganglioside antibodies: anti-GM1 (AMAN), anti-GQ1b (Miller Fisher); not always positive and results may take time
• Campylobacter serology/stool culture: preceding infection
• HIV test: HIV seroconversion can cause GBS-like picture
• U&Es, LFTs: baseline

Imaging

• MRI spine with gadolinium: enhance nerve roots (may show enhancement); exclude compressive myelopathy

Acute Treatment

• IVIg 0.4 g/kg/day × 5 days: first-line in UK; equally effective to plasma exchange; easier to administer
• Plasma exchange: 5 exchanges over 10-14 days; equally effective; preferred if IVIg contraindicated
• Steroids are NOT effective in GBS (unlike CIDP) - do NOT give
• Combination IVIg + PE is NOT more effective than either alone

Monitoring

• ITU/HDU admission for: bulbar dysfunction, FVC <20 mL/kg or declining, autonomic instability
• Serial FVC Q4-6h (even more frequently if declining)
• Continuous cardiac monitoring (autonomic dysfunction - arrhythmias)
• VTE prophylaxis: LMWH (enoxaparin 40 mg OD SC) + compression stockings

Supportive

• Respiratory: intubation and ventilation if FVC <15-20 mL/kg; ~25% require mechanical ventilation
• Pain management: paracetamol, gabapentin 300-3600 mg/day, opioids if severe
• DVT prophylaxis: LMWH
• Physiotherapy: early rehabilitation; passive exercises to prevent contractures
• Nutrition: nasogastric feeding if bulbar weakness
• Psychological support: anxiety, depression common in prolonged illness

Referral Criteria

• All suspected GBS: emergency neurology admission
• Declining FVC: ITU involvement immediately

~80% make a good or complete recovery (may take months to years). ~5% mortality (respiratory failure, autonomic dysfunction, PE). ~20% have significant residual disability at 1 year. ~5-10% develop CIDP (relapsing course >8 weeks). Predictors of poor outcome: older age, rapid onset, axonal variant (AMAN/AMSAN), preceding Campylobacter infection, need for ventilation. Erasmus GBS Outcome Score (EGOS) predicts ability to walk at 6 months.

GBS Subtypes

Indicators for Intubation

Key Facts

CIDP is the most common chronic acquired demyelinating neuropathy. Unlike GBS, steroids are effective. Many patients require long-term immunotherapy. Early treatment prevents irreversible axonal damage.

Epidemiology

Prevalence ~2-5 per 100,000. Mean onset 40-60 years. M:F 2:1. Accounts for ~5% of all neuropathies referred to specialist centres.

Aetiology

• Autoimmune: cell-mediated and humoral immune mechanisms target peripheral nerve myelin
• Associated with: diabetes mellitus, paraproteinaemias (IgG, IgA, IgM - check SPEP), hepatitis C, HIV, inflammatory bowel disease, connective tissue disease
• Some patients have anti-NF155, anti-CNTN1, or anti-Caspr1 antibodies ("nodopathies" - may respond differently to treatment)

Pathophysiology

Immune-mediated segmental demyelination and remyelination of peripheral nerves and nerve roots. Both T-cell and macrophage-mediated stripping of myelin sheaths and complement-mediated damage. Chronic demyelination leads to secondary axonal degeneration (irreversible - hence importance of early treatment). Onion bulb formation on nerve biopsy (repeated demyelination/remyelination cycles).

Typical CIDP

• Progressive symmetric proximal AND distal weakness: develops over >8 weeks; legs and arms affected; both proximal and distal (unlike most neuropathies which are length-dependent/distal)
• Areflexia or hyporeflexia: global
• Sensory loss: large-fibre predominant (vibration, proprioception); sensory ataxia; paraesthesiae
• Course: progressive (~65%) or relapsing-remitting (~35%)

Atypical Variants

• Distal variant (DADS): distal acquired demyelinating symmetric neuropathy; often with IgM paraprotein and anti-MAG antibodies
• Multifocal variant (Lewis-Sumner): asymmetric, upper limb predominant; sensory + motor
• Pure sensory CIDP: sensory ataxia without weakness
• Pure motor CIDP: weakness without sensory loss

Red Flags

• Progressive weakness over >8 weeks (not self-limiting like GBS)
• Proximal AND distal weakness (unusual for most neuropathies)
• Relapsing course in a neuropathy

Neurophysiology (Essential)

• NCS: demyelinating features in ≥2 nerves: prolonged distal motor latencies (>50% above ULN), reduced motor conduction velocities (<70% of LLN), conduction block (>50% CMAP amplitude drop), temporal dispersion, prolonged/absent F-waves
• Meets EFNS/PNS electrodiagnostic criteria for definite, probable, or possible CIDP

CSF

• Raised protein (often >0.45 g/L) with normal cell count (albuminocytological dissociation)
• Cell count >10/μL → consider alternative (HIV, lymphoma, sarcoid)

Bloods

• SPEP and immunofixation: exclude paraprotein (IgM paraprotein + anti-MAG → different treatment approach)
• HbA1c, glucose: diabetes (coexistent or causative)
• FBC, U&Es, LFTs, TFTs: baseline
• HIV, hepatitis B/C: associated infections
• Anti-NF155, anti-CNTN1 antibodies: specialist; nodopathies

Imaging

• MRI spine: nerve root enhancement (hypertrophy); supports diagnosis but not specific
• Nerve ultrasound: nerve enlargement at non-entrapment sites - increasingly used

Other

• Nerve biopsy (sural nerve): rarely needed; shows demyelination, remyelination (onion bulbs), inflammatory infiltrates; reserve for atypical cases

First-Line (All Three Effective)

• Corticosteroids: prednisolone 60 mg OD (or pulsed IV methylprednisolone 500 mg-1 g daily × 3 days monthly); taper once response achieved
• IVIg: 0.4 g/kg/day × 5 days (2 g/kg total) loading; then maintenance 1 g/kg every 3-4 weeks; titrate to lowest effective dose
• Plasma exchange: 5 exchanges; effective but requires regular vascular access

Second-Line (Steroid-Sparing)

• Azathioprine 2-3 mg/kg/day
• Mycophenolate mofetil 1-3 g/day
• Ciclosporin, methotrexate

Refractory

• Rituximab: especially for anti-MAG or nodopathy variants
• SCIg (subcutaneous immunoglobulin): alternative to IVIg for maintenance; patient self-administers

Rehabilitation

• Physiotherapy, occupational therapy, orthotics (foot drop)
• Falls prevention

Referral Criteria

• All suspected CIDP: neurology (neuromuscular specialist)
• Consider trial of treatment cessation periodically to assess ongoing need

~60-80% respond to first-line treatment (steroids, IVIg, or PE). Relapsing-remitting course: generally better prognosis than progressive. ~10% become treatment-refractory. Early treatment prevents irreversible axonal damage and disability. Long-term IVIg dependence in ~50%. Complete remission in ~10-20%. Anti-MAG neuropathy: often more refractory to standard treatment. Nodopathies (anti-NF155): may respond to rituximab better than IVIg.

CIDP vs GBS

EFNS/PNS CIDP Diagnostic Criteria (Simplified)

Key Facts

Peripheral neuropathy is extremely common. Systematic approach to classification (fibre type, distribution, pathology, tempo) narrows the differential efficiently. NCS/EMG is essential for distinguishing axonal from demyelinating neuropathy.

Epidemiology

Prevalence ~2-3% (up to 8% in over-55s). Diabetic neuropathy affects ~50% of diabetic patients. Alcohol-related neuropathy in ~10% of chronic alcoholics. ~25% remain idiopathic despite investigation (chronic idiopathic axonal polyneuropathy - CIAP).

Aetiology

Common causes by pattern:

• Distal symmetric polyneuropathy (commonest): diabetes (most common overall), alcohol, B12 deficiency, drugs (chemotherapy - cisplatin, vincristine, taxanes; isoniazid; amiodarone; metformin-induced B12 deficiency), chronic kidney disease, hypothyroidism
• Mononeuritis multiplex: vasculitis (PAN, GPA, EGPA), diabetes, sarcoidosis, leprosy, amyloidosis, paraneoplastic
• Demyelinating neuropathy: CIDP, GBS, CMT (hereditary), anti-MAG paraprotein
• Small fibre neuropathy: diabetes, amyloidosis, Fabry disease, sarcoidosis (NCS may be normal)

Pathophysiology

Axonal degeneration: damage to the axon itself (dying-back pattern - distal to proximal); NCS shows reduced CMAP/SNAP amplitudes with preserved conduction velocities. Causes: metabolic, toxic, nutritional. Demyelination: damage to the myelin sheath; NCS shows reduced conduction velocities, prolonged distal latencies, conduction block. Causes: immune-mediated (CIDP, GBS), hereditary (CMT).

Sensory Neuropathy

• Large-fibre loss: numbness, tingling, loss of vibration/proprioception, sensory ataxia (positive Romberg), absent ankle jerks
• Small-fibre loss: burning pain, dysaesthesia, reduced pain/temperature sensation; autonomic features; NCS may be NORMAL

Motor Neuropathy

• Distal weakness: foot drop (common peroneal), wrist drop (radial), hand weakness
• Muscle wasting, fasciculations (if LMN affected)

Autonomic Neuropathy

• Postural hypotension, resting tachycardia, gustatory sweating, erectile dysfunction, gastroparesis, constipation/diarrhoea, bladder dysfunction

Key Patterns

• Glove-and-stocking: length-dependent; diabetes, alcohol, B12
• Mononeuritis multiplex: painful, asymmetric, multiple named nerves; vasculitis
• Proximal + distal weakness: CIDP, GBS

Red Flags

• Rapidly progressive weakness → GBS
• Mononeuritis multiplex → vasculitis (urgent investigation)
• Weight loss + neuropathy → malignancy, amyloidosis
• Young patient with neuropathy → hereditary (CMT), Fabry disease
• Predominant motor neuropathy → think CIDP, multifocal motor neuropathy

Bedside

• Neurological examination: sensory modalities (light touch, pinprick, vibration, proprioception), power, reflexes, gait (Romberg)
• Monofilament testing: 10g monofilament for diabetic foot screening

Bloods (First-Line)

• HbA1c / fasting glucose: diabetes
• FBC: macrocytosis (B12, alcohol)
• B12 and folate: deficiency
• TFTs: hypothyroidism
• U&Es: renal failure
• LFTs and GGT: alcohol
• SPEP + immunofixation: paraprotein
• ESR/CRP: vasculitis, infection

Bloods (Second-Line - Guided by Clinical Suspicion)

• ANCA, ANA, dsDNA, complement: vasculitis
• HIV, hepatitis B/C: infectious causes
• Anti-neuronal antibodies: paraneoplastic
• Serum ACE: sarcoidosis
• Urine Bence Jones: myeloma
• Alpha-galactosidase A: Fabry disease (young patients)

Neurophysiology

• NCS/EMG: essential; distinguishes axonal from demyelinating; identifies mononeuritis multiplex pattern; guides further investigation

Special Tests

• Nerve biopsy (sural): vasculitis, amyloidosis, sarcoidosis; rarely needed
• Skin biopsy: intraepidermal nerve fibre density - gold standard for small fibre neuropathy
• Genetic testing: CMT (PMP22 duplication for CMT1A)
• Lumbar puncture: if CIDP/GBS suspected

Treat Underlying Cause

• Diabetes: optimise glycaemic control (NICE NG28)
• B12 deficiency: hydroxocobalamin 1 mg IM on alternate days × 2 weeks, then every 2-3 months
• Alcohol: abstinence, thiamine supplementation (Pabrinex IV initially, then oral thiamine 100 mg TDS)
• Drug-induced: stop or reduce offending agent
• CIDP: immunotherapy (see CIDP section)
• Vasculitis: immunosuppression (steroids ± cyclophosphamide)

Neuropathic Pain Management (NICE CG173)

• First-line: amitriptyline 10-75 mg ON, duloxetine 60-120 mg OD, gabapentin 300-3600 mg/day, or pregabalin 150-600 mg/day
• Second-line: combination of above; tramadol for acute rescue
• Topical: capsaicin 0.075% cream, lidocaine 5% plasters (localised neuropathic pain)
• Specialist: referral to pain clinic for refractory neuropathic pain

Rehabilitation

• Physiotherapy: gait training, balance, falls prevention
• Orthotics: ankle-foot orthoses for foot drop
• Occupational therapy: adaptive devices

Referral Criteria

• Neurology: diagnostic uncertainty, suspected CIDP/vasculitis, atypical features, progressive motor neuropathy
• Rapidly progressive or mononeuritis multiplex: urgent referral

Depends on cause. Diabetic neuropathy: progressive if glycaemic control poor; pain may improve with good control. B12 deficiency: partially reversible if treated early (neurological damage may be permanent if delayed). CIDP: ~80% respond to treatment. Idiopathic neuropathy (CIAP): generally slowly progressive, minimal disability. Vasculitic neuropathy: prognosis depends on underlying disease and treatment response.

Axonal vs Demyelinating Neuropathy

Causes of Mononeuritis Multiplex (Exam Favourite)

Key Facts

Diabetic neuropathy is the commonest microvascular complication of diabetes. It is the leading cause of non-traumatic amputation in the UK. Prevention through glycaemic control and early detection through annual screening are the most important interventions.

Epidemiology

Prevalence: ~50% of diabetic patients have some form of neuropathy; ~25% have painful neuropathy. Risk increases with duration of diabetes, poor glycaemic control, and presence of other microvascular complications. Both T1DM and T2DM affected.

Aetiology

• Hyperglycaemia is the primary driver; duration of exposure correlates with risk
• Other risk factors: dyslipidaemia, hypertension, smoking, obesity, genetic susceptibility
• Metabolic syndrome components independently contribute

Pathophysiology

Multiple interconnected pathways driven by chronic hyperglycaemia:

• PKC activation: vascular dysfunction, reduced endoneurial blood flow
• Hexosamine pathway: altered gene expression
• Oxidative/nitrosative stress: mitochondrial dysfunction, DNA damage
• Microvascular disease: endoneurial hypoxia from vasa nervorum disease
• Result: progressive axonal degeneration (dying-back pattern) and segmental demyelination

Distal Symmetric Polyneuropathy (DSPN - ~75%)

• Gradual onset; sensory > motor; glove-and-stocking distribution
• Numbness, tingling, burning pain (worse at night), impaired vibration/proprioception
• Absent ankle jerks; loss of 10g monofilament sensation
• May be asymptomatic - hence importance of annual screening

Painful Diabetic Neuropathy

• Burning, lancinating, shooting pain; allodynia; hyperalgesia
• Worse at night; disrupts sleep
• May occur paradoxically with improvement in glycaemic control ("insulin neuritis" or treatment-induced neuropathy)

Autonomic Neuropathy

• Cardiovascular: resting tachycardia, orthostatic hypotension, exercise intolerance, silent MI
• GI: gastroparesis (nausea, vomiting, early satiety), constipation, diarrhoea (often nocturnal)
• GU: erectile dysfunction, neurogenic bladder
• Sudomotor: gustatory sweating, anhidrosis (feet)

Other Forms

• Diabetic amyotrophy (proximal motor neuropathy): painful wasting of thigh muscles; often asymmetric; weight loss; usually self-limiting over 12-18 months
• Cranial mononeuropathy: CN III palsy (pupil-sparing - distinguishes from compressive cause); CN VI, VII
• Mononeuritis multiplex: painful; multiple named nerves affected sequentially

Red Flags

• Loss of protective sensation → high amputation risk
• Autonomic neuropathy with silent MI risk
• Rapid asymmetric weakness (exclude other causes)
• Charcot foot (hot, swollen, painless joint destruction)

Bedside

• 10g monofilament testing: annual diabetic foot screening (NICE NG19)
• Vibration perception (128 Hz tuning fork): reduced at great toe
• Ankle reflexes: absent in DSPN
• Ipswich Touch Test: simple screening alternative to monofilament

Bloods

• HbA1c: current glycaemic control
• B12: metformin-induced deficiency (check in all diabetic patients on metformin with neuropathy)
• U&Es: renal function (concurrent diabetic nephropathy)
• TFTs: coexistent hypothyroidism
• SPEP: exclude paraprotein

Neurophysiology

• NCS: axonal sensorimotor polyneuropathy; reduced SNAP/CMAP amplitudes distally with relatively preserved conduction velocities
• Not routinely required for typical DSPN but useful if diagnostic uncertainty

Autonomic Testing

• Lying/standing BP: orthostatic hypotension (>20 mmHg systolic drop)
• Heart rate variability: reduced R-R interval variation (Valsalva, deep breathing)
• Gastric emptying study: if gastroparesis suspected

Foot Assessment

• Annual comprehensive foot exam (NICE NG19): risk stratification for ulceration/amputation

Prevention (Most Important)

• Optimise glycaemic control: target HbA1c individualised (NICE NG28); tight control reduces neuropathy by ~60% in T1DM (DCCT/EDIC) and significantly in T2DM (UKPDS)
• Cardiovascular risk management: BP control, lipids, smoking cessation

Painful Diabetic Neuropathy (NICE CG173)

• First-line: amitriptyline 10-75 mg ON, duloxetine 60-120 mg OD, gabapentin 300-3600 mg/day, or pregabalin 150-600 mg/day
• Duloxetine has specific evidence for painful diabetic neuropathy (NICE preferred in T2DM with concurrent depression)
• Combination therapy: if monotherapy inadequate
• Topical: capsaicin 0.075% cream for localised pain
• Specialist referral: pain clinic for refractory cases; consider tramadol as rescue

Autonomic Neuropathy

• Orthostatic hypotension: fludrocortisone 100-300 μg OD, midodrine 2.5-10 mg TDS; compression stockings; slow positional changes
• Gastroparesis: domperidone 10 mg TDS (short-term), metoclopramide 10 mg TDS (short-term; avoid long-term - tardive dyskinesia); dietary modification (small frequent meals)
• Erectile dysfunction: PDE5 inhibitors (sildenafil 25-100 mg)

Diabetic Foot Care (NICE NG19)

• Annual risk assessment and foot exam
• Podiatry: nail care, callus management, footwear advice
• Patient education: daily foot checks, appropriate footwear
• Prompt treatment of foot ulcers (MDT - diabetic foot team)

Referral Criteria

• Diabetic foot team: any ulceration, Charcot foot, ischaemia
• Neurology: atypical features, diagnostic uncertainty
• Pain clinic: refractory neuropathic pain

DSPN is generally slowly progressive. Tight glycaemic control slows but does not reverse established neuropathy. Painful neuropathy may spontaneously improve in some patients (but nerve damage progresses). Diabetic foot ulceration: lifetime risk ~25%; 5-year mortality after diabetic amputation ~50% (comparable to many cancers). Autonomic neuropathy: associated with increased cardiovascular mortality (silent MI, sudden death - 5-year mortality ~25-50% if symptomatic cardiac autonomic neuropathy).

Types of Diabetic Neuropathy

Key Trials

Key Facts

CTS is the commonest peripheral nerve entrapment. Diagnosis is clinical, confirmed by NCS. Most patients respond to conservative or surgical treatment. Exclude underlying causes.

Epidemiology

Lifetime prevalence ~5-10%. Annual incidence ~3 per 1,000. F:M 3:1. Peak age 40-60 years. Bilateral in ~50%. Pregnancy-associated CTS: up to 50% (resolves postpartum in most).

Aetiology

• Idiopathic (most common): combination of anatomical and repetitive strain factors
• Conditions increasing carpal tunnel contents: flexor tenosynovitis (RA, overuse), ganglion cysts
• Conditions reducing carpal tunnel volume: fracture/dislocation (Colles, scaphoid)
• Systemic associations: pregnancy, hypothyroidism, diabetes mellitus, obesity, RA, acromegaly, amyloidosis (especially dialysis-related β2-microglobulin), gout

Pathophysiology

Symptoms

• Pain and paraesthesiae: in median nerve distribution (thumb, index, middle, radial half of ring finger); often described as burning, tingling, numbness
• Nocturnal predominance: wakes patient from sleep; relieved by shaking or hanging hand over bed ("flick sign")
• Clumsiness: difficulty with fine motor tasks (buttons, holding objects)
• Radiation: pain may radiate to forearm, occasionally to upper arm/shoulder

Signs

• Sensory loss: in median nerve distribution (lateral 3½ digits palmar aspect)
• Thenar wasting: in advanced/severe disease (abductor pollicis brevis, opponens pollicis)
• Weakness of thumb abduction/opposition: late sign
• Tinel sign: tapping over carpal tunnel reproduces paraesthesiae (sensitivity ~50%)
• Phalen test: maximal wrist flexion for 60 seconds reproduces symptoms (sensitivity ~70%)
• Durkan test: direct compression over carpal tunnel for 30 seconds

Red Flags

• Thenar wasting (severe - needs urgent intervention)
• Bilateral CTS in young patient → think acromegaly, amyloidosis
• CTS + other neuropathies → systemic cause
• Post-traumatic CTS → acute carpal tunnel syndrome (surgical emergency)

Nerve Conduction Studies (Gold Standard)

• Median nerve sensory latency prolonged across wrist (>3.5 ms); reduced SNAP amplitude
• Median nerve motor latency prolonged (>4.2 ms to APB); reduced CMAP amplitude in severe
• Comparison with ulnar nerve latency increases sensitivity
• Sensitivity ~85-90%; specificity ~95%

Bloods (Screen for Underlying Cause)

• TFTs: hypothyroidism
• HbA1c: diabetes
• ESR/CRP, RF: rheumatoid arthritis
• U&Es: renal failure (dialysis-related amyloidosis)
• Pregnancy test: if appropriate

Imaging

• Wrist ultrasound: increased median nerve cross-sectional area at the wrist (>10 mm²); increasingly used as an adjunct
• MRI wrist: rarely needed; for space-occupying lesions or atypical cases
• X-ray wrist: if bony cause suspected (fracture, osteoarthritis)

Conservative (First-Line)

• Night wrist splint: neutral position; NICE CKS recommends as first-line; 4-6 weeks trial; effective in ~80% of mild-moderate cases
• Activity modification: avoid repetitive wrist flexion/extension, ergonomic assessment
• Corticosteroid injection: methylprednisolone 40 mg or triamcinolone 40 mg injected into carpal tunnel (ultrasound-guided improves accuracy); provides relief in ~70% but recurrence common (~50% at 1 year)

Surgical (Definitive)

• Carpal tunnel release (decompression): division of the flexor retinaculum; open or endoscopic approach
• Indications: failed conservative treatment, moderate-severe NCS findings, thenar wasting, constant numbness, acute CTS (post-trauma)
• Success rate ~90-95%; low complication rate
• NICE: refer for surgery if conservative management fails after 3-6 months, or if severe (thenar wasting, constant numbness)

Pregnancy-Related CTS

• Wrist splint first-line; most resolve postpartum within 3-6 months
• Avoid steroid injection if possible during pregnancy
• Surgery rarely needed

Referral Criteria

• Hand surgery/neurosurgery: failed conservative treatment, thenar wasting, severe NCS
• Neurology: diagnostic uncertainty, atypical features
• Endocrinology: if underlying hormonal cause identified

Mild CTS: ~30-40% resolve spontaneously. Splinting effective in ~80% of mild-moderate cases. Steroid injection: ~70% initial improvement; ~50% relapse within 1 year. Surgical decompression: ~90-95% success rate; most patients experience significant symptom relief within 6 weeks. Delayed treatment with thenar wasting may not fully recover muscle bulk. Pregnancy-related: ~90% resolve within 3-6 months postpartum.

Median Nerve - Key Anatomy

CTS Severity Grading (NCS)

Key Facts

Migraine is a highly prevalent neurological condition causing substantial disability. Accurate diagnosis, avoidance of medication overuse, and appropriate use of both acute and preventive therapies are key to management.

Epidemiology

Prevalence ~15% in UK (~10 million people). F:M 3:1 (hormonal influence - prevalence equalises before puberty and after menopause). Peak age 25-55 years. Migraine is the 6th most disabling condition worldwide (Global Burden of Disease). Economic impact: ~25 million workdays lost per year in UK.

Aetiology

• Genetic predisposition: polygenic; first-degree relatives have 2-3× increased risk; familial hemiplegic migraine (FHM) - rare monogenic forms (CACNA1A, ATP1A2, SCN1A)
• Triggers: stress, sleep disruption, menstruation, alcohol (red wine), certain foods (cheese, chocolate, caffeine withdrawal), bright lights, weather changes, skipping meals
• Hormonal: menarche, menstruation (menstrual migraine), OCP, pregnancy (often improves), menopause

Pathophysiology

Migraine is a neurovascular disorder, NOT simply a vascular headache:

• Cortical spreading depression (CSD): wave of neuronal depolarisation across cortex → aura symptoms; triggers trigeminal activation

• Central sensitisation: repeated trigeminal activation → allodynia, photophobia, phonophobia
• Brainstem activation: PAG (periaqueductal grey), locus coeruleus, raphe nuclei - "migraine generator"
• CGRP is the key mediator (basis for CGRP-targeted therapies)

Migraine Without Aura (ICHD-3 Criteria)

• ≥5 attacks fulfilling criteria
• Headache lasting 4-72 hours (untreated)
• ≥2 of: unilateral, pulsating, moderate-severe, aggravated by routine physical activity
• ≥1 of: nausea/vomiting, photophobia AND phonophobia

Migraine With Aura (ICHD-3 Criteria)

• ≥2 attacks with aura fulfilling criteria
• Aura: fully reversible visual (zigzag lines/fortification spectra, scotoma - most common), sensory (tingling, numbness), or speech/language symptoms
• ≥3 of: aura develops gradually over ≥5 min, 2+ symptoms occur in succession, each symptom lasts 5-60 min, ≥1 symptom is unilateral, aura accompanied/followed by headache within 60 min

Other Subtypes

• Chronic migraine: ≥15 headache days/month for ≥3 months (≥8 meeting migraine criteria)
• Menstrual migraine: occurs within 2 days of onset of menstruation; purely menstrual vs menstrually-related
• Hemiplegic migraine: motor weakness as part of aura (may mimic stroke)
• Migraine with brainstem aura: vertigo, dysarthria, tinnitus, diplopia, decreased consciousness

Red Flags (SNOOP)

• Systemic symptoms (fever, weight loss, cancer, HIV)
• Neurological signs (focal deficit persisting after headache)
• Onset sudden (thunderclap - SAH until proven otherwise)
• Older (new onset >50 years - GCA, space-occupying lesion)
• Pattern change (progressive worsening, change in character)

Clinical Diagnosis

• Migraine is a clinical diagnosis based on ICHD-3 criteria; no investigation required for typical presentation
• Headache diary: essential for tracking frequency, triggers, medication use

When to Investigate (Red Flags)

• CT head (urgent): thunderclap headache (exclude SAH)
• MRI brain: atypical features, new onset >50, focal neurological signs, progressive headache, seizures
• LP: after CT if SAH suspected (xanthochromia at 12 hours); raised CSF pressure (IIH)
• ESR/CRP: if >50 years → exclude GCA

Bloods (Rarely Needed)

• Only if secondary cause suspected: ESR, CRP, TFTs, FBC

Acute Treatment (NICE CG150)

• Mild-moderate: aspirin 900 mg or ibuprofen 400 mg + antiemetic if needed
• Moderate-severe: oral triptan (sumatriptan 50-100 mg, zolmitriptan 2.5-5 mg, rizatriptan 10 mg) + NSAID (ibuprofen 400 mg) or paracetamol 1g
• Antiemetics: metoclopramide 10 mg, prochlorperazine 10 mg (also enhances analgesic absorption)
• SC sumatriptan 6 mg: for rapid onset/vomiting; nasal sumatriptan/zolmitriptan alternatives
• Triptans contraindicated in: uncontrolled HTN, IHD, cerebrovascular disease, peripheral vascular disease, hemiplegic migraine, migraine with brainstem aura
• Avoid opioids: risk of MOH, poor efficacy
• Medication overuse: limit acute treatments to ≤10 days/month (triptans/opioids) or ≤15 days/month (simple analgesics)

Preventive Treatment (≥2 Attacks/Month or Significant Disability)

• First-line (NICE CG150): propranolol 40-240 mg/day (contraindicated in asthma) or topiramate 25-100 mg/day (teratogenic - PPP; side effects: weight loss, cognitive impairment, paraesthesiae, renal stones)
• Amitriptyline 10-50 mg ON (off-label; good if coexistent tension-type headache or insomnia)
• Candesartan 8-16 mg OD (off-label; good evidence)
• Menstrual migraine: frovatriptan 2.5 mg BD (perimenstrual - 2 days before onset for 5-7 days); consider continuous OCP or desogestrel for hormonal manipulation

CGRP-Targeted Therapies (NICE TA)

• Erenumab 70-140 mg SC monthly (anti-CGRP receptor; NICE TA764)
• Fremanezumab 225 mg SC monthly or 675 mg quarterly (anti-CGRP; NICE TA764)
• Galcanezumab 120 mg SC monthly (anti-CGRP; NICE TA919)
• Indicated for chronic migraine (≥15 days/month) with ≥3 prior preventive treatment failures; or episodic migraine with ≥4 days/month and ≥3 prior failures

Other

• Botulinum toxin A (onabotulinumtoxinA): PREEMPT protocol for chronic migraine; NICE TA260; 155 units across 31 injection sites; every 12 weeks
• Greater occipital nerve block: local anaesthetic ± steroid; evidence for refractory migraine

Non-Pharmacological

• Identify and avoid triggers (diary)
• Regular sleep, meals, hydration, exercise
• CBT, mindfulness, biofeedback
• Acupuncture: NICE recommends as an option for prophylaxis

Referral Criteria

• Headache clinic/neurology: diagnostic uncertainty, chronic migraine, medication overuse headache, failure of ≥2 preventives
• Emergency: thunderclap headache, new neurological deficit, papilloedema

Migraine is a lifelong condition for most; ~50% of patients have significant improvement by their 50s. Chronic migraine develops in ~3% of episodic migraine patients per year (risk factors: medication overuse, obesity, depression, high attack frequency). CGRP antibodies and botulinum toxin have transformed outcomes for chronic migraine. Migraine with aura carries a modestly increased risk of ischaemic stroke (especially in women who smoke and take the combined OCP - avoid COCP in migraine with aura).

Migraine Preventive Medications Comparison

Combined OCP and Migraine

Key Facts

TTH is the most prevalent headache disorder globally. It is often underdiagnosed as patients may not seek medical attention. Chronic TTH can be significantly disabling and may overlap with medication overuse headache.

Epidemiology

Lifetime prevalence 30-80%. More common in women (F:M 1.5:1). Peak prevalence in 30s-40s. Chronic TTH affects ~3% of the population.

Aetiology

• Multifactorial: stress, poor posture, anxiety, depression, sleep disruption, jaw clenching, eye strain
• Chronic TTH: central sensitisation plays a key role
• Genetic factors contribute (~40% concordance in twin studies)

Pathophysiology

Episodic TTH: peripheral mechanisms predominate - increased pericranial myofascial tenderness, nociceptive input from pericranial muscles. Chronic TTH: central sensitisation of second-order neurones in the trigeminal nucleus caudalis → enhanced pain perception; reduced descending inhibition. Peripheral and central mechanisms operate on a continuum from episodic to chronic TTH.

Typical Features (ICHD-3)

• Bilateral, pressing/tightening (non-pulsating) quality
• Mild-moderate intensity (does NOT prevent activity - patients can continue work)
• NOT aggravated by routine physical activity
• Duration 30 minutes to 7 days
• No nausea/vomiting (mild nausea allowed in chronic TTH)
• Photophobia OR phonophobia (not both) or neither

Subtypes

• Infrequent episodic: <1 day/month
• Frequent episodic: 1-14 days/month for ≥3 months
• Chronic: ≥15 days/month for >3 months

Associated Features

• Pericranial muscle tenderness on palpation
• Stress, anxiety, depression frequently coexist

Red Flags (Same SNOOP Criteria as Migraine)

• Thunderclap onset, fever, focal neurological signs, papilloedema, new onset >50 years, progressive worsening

Clinical Diagnosis

• TTH is a clinical diagnosis - no investigations needed for typical presentation
• Headache diary: useful to classify frequency and identify medication overuse

When to Investigate

• Red flag features: CT/MRI brain
• New onset >50 years: ESR, CRP (exclude GCA)
• Chronic daily headache: consider MRI to exclude secondary causes
• Papilloedema: urgent CT then LP

Acute Treatment

• Paracetamol 1g or ibuprofen 400mg (or aspirin 600-900mg) - simple analgesia
• Avoid codeine/opioid combinations (risk of medication overuse headache)
• Limit acute treatment to <15 days/month (simple analgesics) or <10 days/month (triptans/opioids)

Prophylaxis (Chronic TTH)

• Amitriptyline 10-75mg ON: first-line prophylactic; start at 10mg, titrate slowly; NICE CG150
• Mirtazapine 15-30mg ON: alternative if amitriptyline not tolerated
• Acupuncture: NICE CG150 recommends as option for chronic TTH prophylaxis

Non-Pharmacological

• Stress management, relaxation techniques
• CBT: effective for chronic TTH
• Physiotherapy: cervical spine, posture correction
• Regular exercise, adequate sleep hygiene
• Reduce caffeine intake

Medication Overuse Headache

• Withdraw overused medication (may need abrupt or gradual depending on agent)
• Bridge with alternative if needed

Referral Criteria

• Headache clinic: chronic TTH refractory to treatment, diagnostic uncertainty, medication overuse headache

Episodic TTH: generally benign, self-limiting. ~3% of episodic TTH progresses to chronic TTH per year. Chronic TTH: can be significantly disabling; ~40% remit to episodic over 2 years with treatment. Medication overuse is the most common factor perpetuating chronic TTH. Amitriptyline reduces headache frequency by ~50% in chronic TTH.

Migraine vs Tension-Type Headache